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Targeting cytotoxic lymphocyte antigen 4 (CTLA-4) in breast cancer

European Journal of Medical Research volume 29, Article number: 353 (2024) Cite this article

Abstract

Breast cancer (BC) has a high mortality rate and is one of the most common malignancies in the world. Initially, BC was considered non-immunogenic, but a paradigm shift occurred with the discovery of tumor-infiltrating lymphocytes (TILs) and regulatory T cells (Tregs) in the BC tumor microenvironment. CTLA-4 (Cytotoxic T-lymphocyte-associated protein 4) immunotherapy has emerged as a treatment option for BC, but it has limitations, including suboptimal antitumor effects and toxicity. Research has demonstrated that anti-CTLA-4 combination therapies, such as Treg depletion, cancer vaccines, and modulation of the gut microbiome, are significantly more effective than CTLA-4 monoclonal antibody (mAB) monotherapy. Second-generation CTLA-4 antibodies are currently being developed to mitigate immune-related adverse events (irAEs) and augment antitumor efficacy. This review examines anti-CTLA-4 mAB in BC, both as monotherapy and in combination with other treatments, and sheds light on ongoing clinical trials, novel CTLA-4 therapeutic strategies, and potential utility of biomarkers in BC.

Graphical Abstract

Introduction

Breast cancer, which is one of the most prevalent malignancies and has the fifth-highest mortality rate among all cancers, has traditionally not been considered immunogenic [67, 96]. However, recent studies have indicated the presence of tumor-infiltrating lymphocytes (TIL) and regulatory T (Treg) cells in breast cancer, providing the rationale for immunotherapy as a potential treatment option, particularly for triple-negative breast cancer (TNBC), which currently lacks targeted treatment and is not responsive to standard therapies for a large proportion of patients [45, 105]. Immunotherapy is currently under investigation in the context of breast cancer and the identification of potential biomarkers that may predict the response to treatment.

Tumors co-opt immune checkpoint proteins such as CTLA-4 to create an immunosuppressive tumor microenvironment (TME), circumvent immune surveillance, and promote tumor progression (Fig. 1) [36]. Notably, CTLA-4 is found in T cells, non-lymphoid cells, B cells, dendritic cells, stromal cells, and tumors [60, 72]. CTLA-4 negatively regulates T effector cell function by outcompeting CD28/CD80 co-stimulatory receptors and binding to their shared ligand, B7-1, thereby inhibiting T-cell activation with higher avidity and affinity [16]. CTLA-4 bound to B7-1 weakens the co-stimulatory signal, producing overall immunosuppressive activity [89]. Furthermore, CTLA-4 interferes with the co-stimulatory signal by removing B7-1 ligands from the surface of antigen-presenting cells via trans-endocytosis and trogocytosis (APC). CTLA-4 removal from the surface of APCs reduces T effector cell function and proliferation [83]. Moreover, CTLA-4 indirectly modulates immunosuppression in the tumor microenvironment (TME) by limiting CD4 + T cells' clonal expansion, which is essential for targeting malignant tumor cells through direct killing or enhancing cytotoxic T-cells and B-cells immune response [6, 46, 69, 102]. CD4 + T-cell reduction diminishes pro-inflammatory cytokine levels, including interleukin 2 (IL-2) and tumor necrosis factor α (TNF-α) as observed in many tumors, including BC [37, 43, 72, 98, 123]. Consequently, CTLA-4 dampens T-cell responses by interacting with a network of immune and tumor cells, producing an immunosuppressive environment. Hence, CTLA-4 humanized monoclonal antibodies (mAB) such as ipilimumab and tremelimumab have demonstrated great clinical benefits in many different malignancies, including melanoma, lung carcinoma, and renal cell carcinoma, but not in BC [20, 36, 116]. CTLA-4 mAB’s has suboptimal antitumor activity and high toxicity effect of anti-CTLA-4 monotherapy in BC; thus, anti-CTLA-4 combination therapy is being explored as an alternative for breast cancer [57]. This review will focus on the mechanism of action of anti-CTLA-4 mAB alone and in combination with other therapies in BC, current clinical trials with anti-CTLA-4 in BC patients, and novel therapeutic approaches to enhance the efficacy and minimize the toxicity of anti-CTLA-4 in BC patients.

Fig. 1
figure 1

Extrinsic therapeutic targets for CTLA-4 therapy in breast cancer. CTLA-4 overexpression reduces pro-inflammatory cytokines, T-cell effector differentiation, and antibody-dependent cellular cytotoxicity, resulting in tumor proliferation and metastases of breast cancer

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CTLA-4 blockade depends on several factors including Treg cells, T-cell infiltration, CD8 + T-cell activation, and tumor-associated macrophage (TAMs) recruitment (Fig. 1). Treg cells are a subpopulation of immune cells required for self-tolerance and to prevent autoimmune diseases [102]. They constitutively express CTLA-4, which inhibits CD4 + and CD8 + cytotoxic T cells in the TME [25, 55, 79]. For instance, Treg cell depletion regressed tumors within a month and increased survival by > 80 days in murine models [74, 95]. Similarly, other studies have demonstrated that Treg cell depletion in mice promoted lymphocyte recruitment and decreased tumor growth rate, implicating Treg's role in tumor promotion [17, 39]. Furthermore, a relatively high level of Treg cells in the TME is associated with poor prognosis in various cancer types, including breast cancer [21]. Numerous studies have demonstrated that CTLA-4 therapies deplete tumor resident Treg cells and downregulate cytotoxic T-cell activity [44, 51, 70, 77, 79, 82, 90, 93, 103, 109]. Treg cells mediate immunosuppression through various mechanisms, such as IL-2 depletion and immunosuppressive cytokine production. Notably, the primary mechanism of action of CTLA-4 mAB is antibody-dependent cellular cytotoxicity (ADCC) of Treg cells (Fig. 1) [8, 11, 13, 18, 49, 55, 94, 97, 108]. The efficient antitumor effects of CTLA-4 blockade depend on the ADCC of Treg cells, as CTLA-4 blockade alone without ADCC has insufficient antitumor activity [115]. Another study revealed that ipilimumab has better activity in patients with FcγR variants that enhance ADCC activity, further implicating the importance of ADCC activity in achieving a robust response [111]. Although anti-CTLA-4 mAB effectively promotes tumor regression in some malignancies, it is insufficient in BC [20, 36, 110]. Nevertheless, preclinical studies have shown that anti-CTLA-4 combination therapy can effectively control tumor growth in BC. Taylor et al. [110] demonstrated CTLA-4 and PD-1 blockade, combined with adoptive cell therapy, significantly delayed tumor growth and prolonged survival by stringently depleting Treg cells in TNBC murine models. Conversely, CTLA-4 and PD-1 blockade alone are insufficient to suppress tumor growth [110]. These findings suggest that anti-CTLA-4 combination therapy could effectively suppress aggressive breast tumor growth compared with anti-CTLA-4 alone. Furthermore, efforts are underway to create novel anti-CTLA-4 mABs with a modified fragment crystallizable (FC) region, promoting stringent Treg cell depletion and robust antitumor activity alone. Gan et al. [28] developed a novel anti-CTLA-4 heavy chain antibody (HCAb 4003-1) engineered to enhance Treg cells' depletion. These findings demonstrate HCAb 4003-1 had higher antitumor activity and a shorter serum half-life than ipilimumab, implicating its minimal toxicity effect [28]. Similarly, developed CTLA-4 mABs with a modified FC region, which demonstrated a robust antitumor response associated with ADCC depletion of Treg cells. These antibodies are promising candidates for future generation of anti-CTLA-4 therapies. A significant concern regarding anti-CTLA-4 mAB is its adverse toxic effects [26]. For instance, ipilimumab lysosomally degrades ~ 50% of CTLA-4, causing severe immunotherapy-related adverse effects (irAEs). However, pH-sensitive CTLA-4 antibodies have been developed (HL12 and HL32) that circumvent immune-related adverse events (irAEs) while producing antitumor effects [122]. The pH-sensitive antibodies bound to CTLA-4 dissociate after lysosomal endocytosis and are recycled back to the cell surface, minimizing CTLA-4 degradation and the overall iRAE. In contrast, conventional mAB is bound to CTLA-4 and is subsequently engulfed by lysosomes and degraded, reducing CTLA-4 levels and inducing iRAE [122]. Besides reducing toxicity levels, pH-sensitive antibodies have high bioavailability, enhancing intratumoral Treg cell depletion and ADCC targeting of CTLA-4, thus amplifying their effectiveness [122]. These findings suggest a novel approach for the development of second-generation antibodies targeting CTLA-4 with high potency and minimal toxicity [122].

Anti-CTLA-4 mAB combination therapy in BC

Several studies have shown that targeting multiple immune inhibitory pathways through combination therapy improves anti-CTLA-4 efficacy through several mechanisms [23, 92]. First, it prevents the compensatory upregulation of other inhibitory checkpoint pathways [19]. Second, immune cells are targeted systematically rather than locally through their distinct and complementary roles (i.e., in the lymph node and tumor site) (Fig. 1) [78]. Third, various immune-infiltrating cells (Tregs and TAMS) are targeted, inducing a stronger inflammatory response, which has implications for immunotherapy resistance (Fig. 1) [92]. For instance, studies have shown that targeting both CTLA-4 and PD-1 expands cytotoxic T cells and transforms tumor-associated monocytes and macrophages to a pro-inflammatory (M1) phenotype through increased IFN-γ secretion, producing an inflammatory tumor microenvironment (TME) [5, 19, 62]. Furthermore, a preclinical study demonstrated that CTLA-4 and PD-1 ICI increased CD8 + T-cell intratumoral infiltration compared to anti-CTLA-4 monotherapy, increasing the rate of tumor-free survival in melanoma mouse models by ~ 65% [19]. Overall, the combination of CTLA-4 and PD-1 immune checkpoint inhibitors boosts antitumor efficacy by influencing intratumoral lymphocyte and myeloid cell components [35, 84, 118]. A single-arm clinical study analyzed the efficacy of tremelimumab in combination with durvalumab (a PD-1 inhibitor) in 18 metastatic breast cancer patients with MBC. The cohort had an objective response rate (ORR) of 17% and 0% in the ER + patients and 43% in the TNBC group. However, the benefits of anti-CTLA-4 and anti-PD-1 combination therapy did not outweigh the risks, and the study was terminated in the second phase (Santa-Maria et al. 2017). Another study investigated ipilimumab in combination with nivolumab in advanced chemotherapy-refractory metaplastic breast cancer. Although the study reached its primary endpoint, 65% of patients experienced significant irAEs [2]. By lowering the dosage of ipilimumab or using newer anti-CTLA-4 formulations irAE could be reduced in patients [4, 114].

Although the combination of CTLA-4 and PD-1 mABs proved to be efficacious, it is inadequate for high levels of intratumoral macrophages in advanced stages of cancer [118]. Neoadjuvant anti-CTLA-4 therapy has been reported to provide a robust antitumor immune response compared to ICI alone in aggressive tumors [87]. An ongoing clinical study is investigating neoadjuvant anti-CTLA-4 therapy in TNBC patients (NCT03546686). This study investigated the safety of administering CTLA-4 and PD-1 immunotherapy in combination with cryoablation or standard care in patients with HER2-negative advanced breast cancer following neoadjuvant chemotherapy. Preclinical findings revealed that this treatment induced a robust immunological response against the tumor both locally and systemically [22, 50] (Table 1).

Table 1 Clinical trial testing Anti-CTLA-4 combination therapy in breast cancer patients
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Anti-CTLA-4 mAB in combination with targeted therapy such as chemotherapy, epigenetic modulators, poly (ADP-ribose) polymerase (PARP) inhibitors, and radiotherapy enhances its therapeutic efficacy compared to monotherapy (Fig. 2) [76]. For example, anti-CTLA-4 mAB, in combination with MAPK inhibitors in TNBC, had a stronger antitumor immunity than anti-CTLA-4 mAB alone (Fig. 2). [33] reported that anti-CTLA-4 mAB in combination with Selumetinib, a MEK1/2 small-molecule inhibitor (SMI), abolished the upregulation of immunosuppressive mediators (Cox-2 and Arg1-), whereas anti-CTLA-4 monotherapy increased their expression in TNBC mouse models (Fig. 2) [33]. Similarly, another study reported that anti-CTLA-4 mAB in combination with PI3Kα inhibitor provided synergistic antitumor activity, regressed breast tumors by 60%, and sensitized the tumor to ICI compared to ICI alone (Fig. 2) [119]. These findings provide a rationale for multiple ongoing clinical studies investigating the efficacy and safety of gedatolisib (PI3Kα inhibitor) in combination with anti-CTLA-4 mAB in patients with metastatic BC [119]. A clinical trial is currently underway to examine the impact of combining anti-CTLA-4 mAB with paclitaxel and gedatolisib on both antitumor efficacy and tolerance in breast cancer patients. (Table 1). Another clinical study investigated the effects of tremelimumab in combination with brain radiotherapy and trastuzumab (a HER2 inhibitor) in patients with ER + metastases (NCT02563925) [85]. Furthermore, chemotherapeutic agents such as paclitaxel, doxorubicin, and gemcitabine prime the immune system by suppressing myeloid derived suppressor cells (MDSCs) enhancing the efficacy of anti-CTLA-4 blockade [7, 27 ]. Hence, a phase IIb clinical study assessed liposomal doxorubicin and cyclophosphamide alone and in combination with ipilimumab and nivolumab in patients with BC (NCT03409198) (Table 1). Another example of CTLA-4 combination treatment enhancing efficacy pertains to targeting mutations in Breast Cancer genes1/2 (BRCA1/2), which are genes involved in DNA repair (Fig. 2) [84]. Notably, high levels of T-cell recruitment and immune gene expression characterize BRCA-mutated tumors and correlate with patients' cytotoxic responses to ICI [73]. Studies have demonstrated that breast tumors with BRCA mutations treated with cisplatin elicited an effective antitumor immune response through a high mutational burden [14, 66, 101, 117]. Similarly, combining CTLA-4 mAB, PD1 mAB, and cisplatin in BRCA-deficient breast cancer mouse models resulted in synergistic cytotoxicity. This combination treatment diminished FOXP3 + Treg cell levels and elevated CD4 + and CD8 + T-cell levels (p < 0.05), significantly reducing tumor growth [73]. Similarly, a preclinical study demonstrated that treating BRCA-deficient immunocompetent ovarian cancer models with ipilimumab and veliparib (PARP inhibitor) enhanced IFN-gamma production and T-cell infiltration [38]. Ipilimumab and veliparib led to synergistic antitumor activity, increasing long-term survival in murine models [38]. Furthermore, a phase 1 clinical trial is underway to examine the effects of combining CTLA-4 mAB with PARP inhibitors in patients diagnosed with BRCA-deficient ovarian cancer. The initial findings from this study indicated positive therapeutic outcomes coupled with favorable tolerability (NCT02571725) (Table 1) [3]. Thus, investigating CTLA-4 mAB in combination with PARP inhibitors in patients with BRCA-mutated BC would be promising. In summary, these findings indicate that anti-CTLA-4 personalized therapy has great potential in BC.

Fig. 2
figure 2

Intrinsic therapeutic targets for CTLA-4 combination therapy include tumor antigens, PD-1 receptor, epigenetic modifiers, BRCA1 and BRCA2, and immunosuppressive mediators (COX-2 and ARG-1), in addition to MAPK and PI3K signaling pathways in cancer cells

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Novel immunotherapeutic strategies for targeting CTLA-4

Anti-CTLA-4 and cancer vaccines

Cancer vaccines are an appealing anti-CTLA-4 therapeutic strategy because they enhance immunogenic response and tumor specificity by targeting neoantigens [90]. A previous study demonstrated that combining anti-CTLA-4 mAB and targeting mucin1 (MUC1), a tumor antigen, with cancer vaccines led to synergistic activation and cytotoxic T-cell expansion [56, 65, 71] (Fig. 2). Similarly, an in vivo study demonstrated that anti-CTLA-4 and anti-PD-1 mABs combined with an oncolytic virus (GM-CSF) increased CD8 + T cells and memory T cells and decreased Treg cell levels in TNBC orthotropic immune-competent murine models. Moreover, this combination therapy increased T helper type 1 cell (TH1) inflammatory cytokines, induced tumor cell apoptosis, reduced tumor growth by ~ 50%, and prolonged survival in TNBC murine models [121]. Another study demonstrated that anti-CTLA-4 combined with DNA vaccines also had synergistic effects, resulting in significant tumor regression compared to anti-CTLA-4 monotherapy [90]. Furthermore, clinical trials are testing tremelimumab as an adjuvant for breast cancer vaccines to enhance TIL recruitment and induce potent cytotoxic responses [30] (NCT02643303). The combination of anti-CTLA-4 therapy with cancer vaccines presents therapeutic promise, particularly for breast cancer patients with poor immunogenicity.

Anti-CTLA-4 and microbiome

The efficacy of anti-CTLA-4 therapy also depends on commensal bacteria composition as studies have shown the gut microbiome is involved in breast cancer development and response to therapy [40, 52, 80, 99, 112]. A recent study reported that CTLA-4 blockade, in combination with introducing strains such as Bacteroides fragilis, germ-free, or antibiotics, improved the efficacy of anti-CTLA-4 therapy by further polarizing the TH1 T helper cells [68]. Furthermore, oral administration of probiotics such as Bacteroides fragilis and Burkholderia cepacia improved the irAE toxicity of anti-CTLA-4 therapy [88]. An ongoing clinical trial is examining the gut microbiota in response to ICI in BC patients (NCT02752685) [53]. These preliminary results indicate that gut microbial bacteria influence anti-CTLA-4 efficacy and antitumor response in breast cancer, making the gut microbiome therapeutically relevant for immunotherapy.

Anti-CTLA-4 and epigenetic modulation

CTLA-4 mAB in combination with epigenetic modifiers is another promising therapeutic strategy for enhancing anti-CTLA-4 efficacy [61] (Fig. 2). The expression of CTLA-4, PD-1, and PD-L1 is enhanced by DNA hypomethylating agents [63]. Consistent with this study, Enhancer of Zeste 2 Polycomb Repressive Complex 2 subunit (EZH2), a methyltransferase enzyme, has been reported to be crucial for differentiating and maintaining Treg cells [120]. Notably, anti-CTLA-4 mABs have been reported to increase EZH2 expression in the peripheral T cells of treated patients. EZH2 inhibition in combination with anti-CTLA-4 mAB enhanced the antitumor immune response in murine models, as evidenced by the increased ratio of Treg to T effector cells and enhanced cytotoxicity of T effector cells compared to anti-CTLA-4 monotherapy [31]. Another study reported that histone deacetylase (HDAC) inhibitors combined with anti-CTLA-4 mAB and/or PD-1 mAB downregulated MDSC in murine mammary models, thereby increasing antitumor immunity [47]. Similarly, ICIs with histone deacetylases or DNA methyltransferases treat more than 80% of metastatic TNBC tumors, with MDSCs as the primary target [47]. Furthermore, the combination of anti-CTLA-4 mAB and HDAC inhibitors enhanced CD4 + T-cell infiltration and displayed synergistic antitumor activity [47]. These preclinical observations provide evidence for the rationale of combining epigenetic modulators with anti-CTLA-4 therapy in breast cancer [15, 47, 48, 75] (Table 1).

Future directions for anti-CTLA-4 treatments

Small-molecule CTLA-4: B7-1 inhibitors

While antibodies directed against CTLA-4, such as ipilimumab, have shown considerable effectiveness, small-molecule inhibitors (SMIs) are more advantageous because of their permeability, lower production costs, prolonged half-lives, and organ-specific targeting [100, 107]. CTLA-4 is currently deemed undruggable, with no known binding pocket at the ligand-binding interface [102]. These peptides and allosteric sites for CTLA-4 have yet to be determined through computational techniques such as molecular dynamic simulations [86, 104]. Nevertheless, some SMIs target CTLA-4 indirectly by blocking B7-1 and its interaction with CTLA-4 and CD28 [100] (Table 3). For instance, (8) and (9) target [24, 32]. Huxley et al. [41] also describe small-molecule inhibitors targeting B7-1 with high specificity and low nanomolar affinity [41]. Similarly, these small molecules were reported to antagonize the CTLA-4 interaction by occluding its binding site. Nonetheless, a limitation of these B7-1 SMIs is their capacity to hinder IL-2 secretion, which is necessary for pro-inflammation [41]. Currently, no CTLA-4 SMI is available on the market [100]. The trajectory of CTLA-4 therapy should center on developing SMIs that directly target CTLA-4 or epigenetically, as these agents offer more significant advantages than monoclonal antibodies.

Anti-CTLA-4 therapy biomarkers

One of the biggest pitfalls of the CTLA-4 mAB is its ability to predict which patients will respond to and benefit from treatment (Fig. 3). Patients could be stratified into responsive and non-responsive groups by assessing predictive biomarkers such as single nucleotide polymorphisms (SNP) [29]. For instance, patients harboring CTLA-4 mutations that impair antitumor immunity are more likely to be responsive to anti-CTLA-4 immunotherapy. Moreover, CTLA-4 SNPs have been extensively studied in different cancers, including TNBCs [113]. Notably, specific SNPs in the promoter region of CTLA-4, such as CTLA-4c.49*G, are associated with breast cancer. Individuals with CTLA-4c.49*G alleles exhibit a 1.8-fold higher likelihood of developing breast cancer than those with the A/A genotype making anti-CTLA-4 a promising therapeutical approach for this patient group [12]. Treg cells are another example of potential biomarkers that could be used to elucidate a patient's responsiveness to anti-CTLA-4 therapy, since they modulate antitumor activity by affecting the Treg cell population [42]. Other potential prognostic and predictive biomarkers are TILs within the adjacent tumor stroma or focal areas [10, 123]. Prall et al. [81] reported that TILs and FOX3P + Treg immune cells were indicators of immunogenicity and prognosis in TNBC [81]. Furthermore, tremelimumab shows the highest responsiveness in invasive breast tumors with > 50% lymphocyte infiltration, also known as lymphocyte-predominant breast cancer (LPBC). Furthermore, a correlation exists between the number of tumor-infiltrating lymphocytes (TILs) and disease-free survival [105]. Stanton et al. [105] analyzed 256 TNBC tumors and demonstrated that with every 10% increase in TILs, there was a 17% reduction in the risk of recurrence (p = 0.023, HR 0.83, 95% CI 0.71–0.98) and a 27% decreased risk of death (p = 0.035, HR = 0.73; 95% CI 0.54–0.98) (Sherene [59]). Similarly, other reports have shown that high TILs levels after treatment are associated with good prognosis, as the greater the number of TILs, the more responsive the patients are to immunotherapy and chemotherapy [34, 64]. However, anti-CTLA-4 responsiveness prediction depends on the subtype and localization of TILs. For instance, patients with efficient CD8 + T-cell tumor infiltration had good treatment outcomes. In contrast, patients with accumulated CD8 + T cells in tumor-associated stroma had poor outcomes [1]. Recently, the WHO St. Gallen International Breast Cancer Conference allowed TILs quantification to determine the prognosis of patients with early-stage TNBC [9, 58].

Fig. 3
figure 3

Breast cancer anti-CTLA-4 potential biomarkers; BRCA1/2, CTLA-4 SNPs, tumor-infiltrating lymphocytes

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These biomarkers shed light on the interplay between BC and the immune system, providing information on tumor responsiveness to treatment (Fig. 3). Technological advancements, such as single-cell omics, are promising as they would provide in-depth qualitative information on biomarkers with prognostic and predictive values for BC patients [54]. Overall, CTLA-4 SNP, TILs, and FOX3P + Treg cells are promising predictive biomarkers for anti-CTLA-4 therapy, but much more needs to be elucidated for anti-CTLA-4 personalized therapy in BC patients.

Conclusion

Immunotherapy has revolutionized the treatment of several malignancies, and has only recently entered the treatment landscape of BC. However, the application of anti-CTLA-4 therapy presents challenges, including its limited effectiveness and considerable toxicity. Emerging immunotherapy data have shown that anti-CTLA-4 combination therapy could soon become the standard treatment for BC. Although very few anti-CTLA-4 clinical studies have been performed in patients with BC, this may change with a deeper understanding of CTLA-4 function in cancer immunity. Recent research highlighting anti-CTLA-4 combination strategies, such as Treg cell depletion, utilization of cancer vaccines, and consideration of the gut microbiome, has revealed promising preclinical results that are poised for subsequent investigation in patients. Future directions for anti-CTLA-4 therapy include second-generation antibodies and SMI with minimal irAE toxicities and high potency, and the identification of standard biomarkers for CTLA-4 immunotherapy. Finally, a comprehensive understanding of the role of anti-CTLA-4 mAB’s in cancer immunity is imperative for further immunotherapeutic advancements in patients with breast cancer.

Availability of data and materials

No datasets were generated or analysed during the current study.

References

  1. Aaltomaa S, Lipponen P, Eskelinen M, Kosma V-M, Marin S, Alhava E, Syrjänen K. Lymphocyte infiltrates as a prognostic variable in female breast cancer. Eur J Cancer. 1992;28(4–5):859–64.

    Article  Google Scholar 

  2. Adams S, Othus M, Patel SP, Miller KD, Chugh R, Schuetze SM, Reddy MP. A multicenter phase II Trial of ipilimumab and nivolumab in unresectable or metastatic metaplastic breast cancer: cohort 36 of dual anti–CTLA-4 and anti–PD-1 blockade in rare tumors (DART, SWOG S1609). Clin Cancer Res. 2022;28(2):271–8.

    Article  CAS  PubMed  Google Scholar 

  3. Adams SF, Rixe O, Lee J-H, McCance DJ, Westgate S, Eberhardt SC, Muller C. Phase I study combining olaparib and tremelimumab for the treatment of women with BRCA-deficient recurrent ovarian cancer. J Clin Oncol. 2017;35(15_suppl):e17052–e17052. https://doi.org/10.1200/JCO.2017.35.15_suppl.e17052.

  4. Autio KA, Boni V, Humphrey RW, Naing A. Probody therapeutics: an emerging class of therapies designed to enhance on-target effects with reduced off-tumor toxicity for use in immuno-oncology. Clin Cancer Res. 2020;26(5):984–9.

    Article  CAS  PubMed  Google Scholar 

  5. Beavis PA, Henderson MA, Giuffrida L, Davenport AJ, Petley EV, House IG, John LB. Dual PD-1 and CTLA-4 checkpoint blockade promotes antitumor immune responses through CD4+ Foxp3− cell–mediated modulation of CD103+ dendritic cells. Cancer Immunol Res. 2018;6(9):1069–81.

    Article  CAS  PubMed  Google Scholar 

  6. Borst J, Ahrends T, Bąbała N, Melief CJ, Kastenmüller W. CD4+ T cell help in cancer immunology and immunotherapy. Nat Rev Immunol. 2018;18(10):635–47.

    Article  CAS  PubMed  Google Scholar 

  7. Bracci L, Schiavoni G, Sistigu A, Belardelli F. Immune-based mechanisms of cytotoxic chemotherapy: implications for the design of novel and rationale-based combined treatments against cancer. Cell Death Differ. 2014;21(1):15–25.

    Article  CAS  PubMed  Google Scholar 

  8. Bulliard Y, Jolicoeur R, Windman M, Rue SM, Ettenberg S, Knee DA, Brogdon JL. Activating Fc γ receptors contribute to the antitumor activities of immunoregulatory receptor-targeting antibodies. J Exp Med. 2013;210(9):1685–93.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Burstein HJ, Curigliano G, Loibl S, Dubsky P, Gnant M, Poortmans P, Regan M. Estimating the benefits of therapy for early-stage breast cancer: the St. Gallen International Consensus Guidelines for the primary therapy of early breast cancer 2019. Ann Oncol. 2019;30(10):1541–57.

    Article  CAS  PubMed  Google Scholar 

  10. Carlomagno N, Incollingo P, Tammaro V, Peluso G, Rupealta N, Chiacchio G, Riccio E. Diagnostic, predictive, prognostic, and therapeutic molecular biomarkers in third millennium: a breakthrough in gastric cancer. BioMed Res Int. 2017. https://doi.org/10.1155/2017/7869802.

    Article  PubMed  PubMed Central  Google Scholar 

  11. Chaudhry A, Rudra D, Treuting P, Samstein RM, Liang Y, Kas A, Rudensky AY. CD4+ regulatory T cells control TH17 responses in a Stat3-dependent manner. Science. 2009;326(5955):986–91.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Chistiakov DA, Savost’anov KV, Turakulov RI, Efremov IA, Demurov LM. Genetic analysis and functional evaluation of the C/T (− 318) and A/G (− 1661) polymorphisms of the CTLA-4 gene in patients affected with Graves’ disease. Clin Immunol. 2006;118(2–3):233–42. https://www.sciencedirect.com/science/article/abs/pii/S152166160500344X?via%3Dihub

  13. Chung Y, Tanaka S, Chu F, Nurieva RI, Martinez GJ, Rawal S, Zhou X-H. Follicular regulatory T cells expressing Foxp3 and Bcl-6 suppress germinal center reactions. Nat Med. 2011;17(8):983–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Clarke B, Tinker AV, Lee C-H, Subramanian S, Van De Rijn M, Turbin D, Cadungog MG. Intraepithelial T cells and prognosis in ovarian carcinoma: novel associations with stage, tumor type, and BRCA1 loss. Mod Pathol. 2009;22(3):393–402.

    Article  CAS  PubMed  Google Scholar 

  15. Clavijo PE, Moore EC, Chen J, Davis RJ, Friedman J, Kim Y, Allen CT. Resistance to CTLA-4 checkpoint inhibition reversed through selective elimination of granulocytic myeloid cells. Oncotarget. 2017;8(34):55804. https://www.oncotarget.com/article/18437/pdf/.

  16. Coillie SV, Wiernicki B, Xu J. Molecular and cellular functions of CTLA-4. Regul Cancer Immune Checkpoints. 2020. p. 7–32.

  17. Colbeck EJ, Jones E, Hindley JP, Smart K, Schulz R, Browne M, Godkin A. Treg depletion licenses T cell–driven HEV neogenesis and promotes tumor destruction. Cancer Immunol Res. 2017;5(11):1005–15.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Collison LW, Workman CJ, Kuo TT, Boyd K, Wang Y, Vignali KM, Vignali DA. The inhibitory cytokine IL-35 contributes to regulatory T-cell function. Nature. 2007;450(7169):566–9.

    Article  CAS  PubMed  Google Scholar 

  19. Curran MA, Montalvo W, Yagita H, Allison JP. PD-1 and CTLA-4 combination blockade expands infiltrating T cells and reduces regulatory T and myeloid cells within B16 melanoma tumors. Proc Natl Acad Sci. 2010;107(9):4275–80.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Darvin P, Toor SM, Nair VS, Elkord E. Immune checkpoint inhibitors: recent progress and potential biomarkers. Exp Mol Med. 2018;50(12):1–11.

    Article  PubMed  Google Scholar 

  21. deLeeuw RJ, Kost SE, Kakal JA, Nelson BH. The prognostic value of FoxP3+ tumor-infiltrating lymphocytes in cancer: a critical review of the literature. Clin Cancer Res. 2012;18(11):3022–9.

    Article  CAS  PubMed  Google Scholar 

  22. Dewan MZ, Galloway AE, Kawashima N, Dewyngaert JK, Babb JS, Formenti SC, Demaria S. Fractionated but not single-dose radiotherapy induces an immune-mediated abscopal effect when combined with anti–CTLA-4 antibody. Clin Cancer Res. 2009;15(17):5379–88.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Disis ML, Stanton SE. Triple-negative breast cancer: immune modulation as the new treatment paradigm. Am Soc Clin Oncol Educ Book. 2015;35(1):e25–30.

    Article  Google Scholar 

  24. Erbe DV, Wang S, Xing Y, Tobin JF. Small molecule ligands define a binding site on the immune regulatory protein B7. 1. J Biol Chem. 2002;277(9):7363–8.

    Article  CAS  PubMed  Google Scholar 

  25. Facciabene A, Peng X, Hagemann IS, Balint K, Barchetti A, Wang L-P, Zhang L. Tumour hypoxia promotes tolerance and angiogenesis via CCL28 and Treg cells. Nature. 2011;475(7355):226–30.

    Article  CAS  PubMed  Google Scholar 

  26. Fellner C. Ipilimumab (yervoy) prolongs survival in advanced melanoma: serious side effects and a hefty price tag may limit its use. Pharm Ther. 2012;37(9):503.

    Google Scholar 

  27. Galluzzi L, Humeau J, Buqué A, Zitvogel L, Kroemer G. Immunostimulation with chemotherapy in the era of immune checkpoint inhibitors. Nat Rev Clin Oncol. 2020;17(12):725–41.

    Article  PubMed  Google Scholar 

  28. Gan X, Shan Q, Li H, Janssens R, Shen Y, He Y, Li J. An anti-CTLA-4 heavy chain–only antibody with enhanced Treg depletion shows excellent preclinical efficacy and safety profile. Proc Natl Acad Sci. 2022;119(32):e2200879119.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Gnjatic S, Bronte V, Brunet LR, Butler MO, Disis ML, Galon J, Khleif SN. Identifying baseline immune-related biomarkers to predict clinical outcome of immunotherapy. J Immunother Cancer. 2017;5(1):1–18.

    Article  Google Scholar 

  30. Gordon B, Gadi VK. The role of the tumor microenvironment in developing successful therapeutic and secondary prophylactic breast cancer vaccines. Vaccines. 2020;8(3):529.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Goswami S, Apostolou I, Zhang J, Skepner J, Anandhan S, Zhang X, Subudhi SK. Modulation of EZH2 expression in T cells improves efficacy of anti–CTLA-4 therapy. J Clin Investig. 2018;128(9):3813–8.

    Article  PubMed  PubMed Central  Google Scholar 

  32. Green NJ, Xiang J, Chen J, Chen L, Davies AM, Erbe D, Tobin JF. Structure–activity studies of a series of dipyrazolo [3, 4-b: 3′, 4′-d] pyridin-3-ones binding to the immune regulatory protein B7. 1. Bioorgan Med Chem. 2003;11(13):2991–3013.

    Article  CAS  Google Scholar 

  33. Grosso JF, Jure-Kunkel MN. CTLA-4 blockade in tumor models: an overview of preclinical and translational research. Cancer Immun Arch. 2013;13(1):5.

    Google Scholar 

  34. Gruosso T, Gigoux M, Bertos N, Manem V, Guiot M-C, Buisseret L, Park M. Distinct immune microenvironments stratify triple-negative breast cancer and predict outcome. Ann Oncol. 2017;28:i16.

    Article  Google Scholar 

  35. Gubin MM, Esaulova E, Ward JP, Malkova ON, Runci D, Wong P, Alspach E. High-dimensional analysis delineates myeloid and lymphoid compartment remodeling during successful immune-checkpoint cancer therapy. Cell. 2018;175(4):1014–30.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Hashimoto M, Kamphorst AO, Im SJ, Kissick HT, Pillai RN, Ramalingam SS, Ahmed R. CD8 T cell exhaustion in chronic infection and cancer: opportunities for interventions. Annu Rev Med. 2018;69:301–18.

    Article  CAS  PubMed  Google Scholar 

  37. Havunen R, Siurala M, Sorsa S, Grönberg-Vähä-Koskela S, Behr M, Tähtinen S, Nettelbeck DM. Oncolytic adenoviruses armed with tumor necrosis factor alpha and interleukin-2 enable successful adoptive cell therapy. Mol Therapy-Oncolytics. 2017;4:77–86.

    Article  CAS  Google Scholar 

  38. Higuchi T, Flies DB, Marjon NA, Mantia-Smaldone G, Ronner L, Gimotty PA, Adams SF. CTLA-4 blockade synergizes therapeutically with PARP inhibition in BRCA1-deficient ovarian cancer. Cancer Immunol Res. 2015;3(11):1257–68. https://cancerimmunolres.aacrjournals.org/content/canimm/3/11/1257.full.pdf.

  39. Hindley JP, Jones E, Smart K, Bridgeman H, Lauder SN, Ondondo B, Withers D. T-cell trafficking facilitated by high endothelial venules is required for tumor control after regulatory T-cell depletion. Can Res. 2012;72(21):5473–82.

    Article  CAS  Google Scholar 

  40. Hooper LV, Littman DR, Macpherson AJ. Interactions between the microbiota and the immune system. Science. 2012;336(6086):1268–73.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Huxley P, Sutton DH, Debnam P, Matthews IR, Brewer JE, Rose J, Classon BJ. High-affinity small molecule inhibitors of T cell costimulation: compounds for immunotherapy. Chem Biol. 2004;11(12):1651–8.

    Article  CAS  PubMed  Google Scholar 

  42. Ignatiadis M, Sledge GW, Jeffrey SS. Liquid biopsy enters the clinic—implementation issues and future challenges. Nat Rev Clin Oncol. 2021. https://doi.org/10.1038/s41571-020-00457-x.

    Article  PubMed  Google Scholar 

  43. Jang D-I, Lee A-H, Shin H-Y, Song H-R, Park J-H, Kang T-B, Yang S-H. The role of tumor necrosis factor alpha (TNF-α) in autoimmune disease and current TNF-α inhibitors in therapeutics. Int J Mol Sci. 2021;22(5):2719.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Ji D, Song C, Li Y, Xia J, Wu Y, Jia J, Gu J. Combination of radiotherapy and suppression of Tregs enhances abscopal antitumor effect and inhibits metastasis in rectal cancer. J Immunother Cancer. 2020;8(2):e000826.

    Article  PubMed  PubMed Central  Google Scholar 

  45. Johnson DB, Nixon MJ, Wang Y, Wang DY, Castellanos E, Estrada MV, Sanchez V. Tumorspecific MHC-II expression drives a unique pattern of resistance to immunotherapy via LAG-3/FCRL6 engagement. JCI Insight. 2018;3(24).

  46. Kennedy R, Celis E. Multiple roles for CD4+ T cells in anti-tumor immune responses. Immunol Rev. 2008;222(1):129–44.

    Article  CAS  PubMed  Google Scholar 

  47. Kim K, Skora AD, Li Z, Liu Q, Tam AJ, Blosser RL, Vogelstein B. Eradication of metastatic mouse cancers resistant to immune checkpoint blockade by suppression of myeloid-derived cells. Proc Natl Acad Sci. 2014;111(32):11774–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Kim SH, Li M, Trousil S, Zhang Y, di Magliano MP, Swanson KD, Zheng B. Phenformin inhibits myeloid-derived suppressor cells and enhances the anti-tumor activity of PD-1 blockade in melanoma. J Investig Dermatol. 2017;137(8):1740–8. https://www.jidonline.org/article/S0022-202X(17)31420-3/pdf.

  49. Koch MA, Tucker-Heard GS, Perdue NR, Killebrew JR, Urdahl KB, Campbell DJ. The transcription factor T-bet controls regulatory T cell homeostasis and function during type 1 inflammation. Nat Immunol. 2009;10(6):595–602.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Kooshkaki O, Derakhshani A, Hosseinkhani N, Torabi M, Safaei S, Brunetti O, Baradaran B. Combination of ipilimumab and nivolumab in cancers: from clinical practice to ongoing clinical trials. Int J Mol Sci. 2020;21(12):4427.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Kvarnhammar AM, Veitonmäki N, Hägerbrand K, Dahlman A, Smith KE, Fritzell S, Smedenfors K. The CTLA-4 x OX40 bispecific antibody ATOR-1015 induces anti-tumor effects through tumor-directed immune activation. J Immunother Cancer. 2019;7(1):1–14.

    Article  Google Scholar 

  52. Kwa M, Plottel CS, Blaser MJ, Adams S. The intestinal microbiome and estrogen receptor–positive female breast cancer. JNCI J Natl Cancer Inst. 2016;108(8):djw029.

    PubMed  Google Scholar 

  53. Kwa MJ, Iwano A, Esteva FJ, Novik Y, Speyer JL, Oratz R, Mendoza S. Phase II trial of pembrolizumab in combination with nab-paclitaxel in patients with metastatic HER2-negative breast cancer. J Clin Oncol. 2017;35(15_suppl):TPS1124–TPS1124. https://doi.org/10.1200/JCO.2017.35.15_suppl.TPS1124.

  54. Lehmann BD, Pietenpol JA. Identification and use of biomarkers in treatment strategies for triple-negative breast cancer subtypes. J Pathol. 2014;232(2):142–50.

    Article  PubMed  PubMed Central  Google Scholar 

  55. Linterman MA, Pierson W, Lee SK, Kallies A, Kawamoto S, Rayner TF, Hogan JJ. Foxp3+ follicular regulatory T cells control the germinal center response. Nat Med. 2011;17(8):975–82.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Liu L, Wang Y, Miao L, Liu Q, Musetti S, Li J, Huang L. Combination immunotherapy of MUC1 mRNA nano-vaccine and CTLA-4 blockade effectively inhibits growth of triple negative breast cancer. Mol Ther. 2018;26(1):45–55.

    Article  CAS  PubMed  Google Scholar 

  57. Liu Y, Zheng P. Preserving the CTLA-4 checkpoint for safer and more effective cancer immunotherapy. Trends Pharmacol Sci. 2020;41(1):4–12.

    Article  CAS  PubMed  Google Scholar 

  58. Loi S. The ESMO clinical practise guidelines for early breast cancer: diagnosis, treatment and follow-up: on the winding road to personalized medicine. Ann Oncol. 2019;30(8):1183–4.

    Article  CAS  PubMed  Google Scholar 

  59. Loi S, Sirtaine N, Piette F, Salgado R, Viale G, Van Eenoo F, Hitre E. Prognostic and predictive value of tumor-infiltrating lymphocytes in a phase III randomized adjuvant breast cancer trial in node-positive breast cancer comparing the addition of docetaxel to doxorubicin with doxorubicin-based chemotherapy: BIG 02–98. J Clin Oncol. 2013;31(7):860–7.

    Article  CAS  PubMed  Google Scholar 

  60. Lüönd F, Tiede S, Christofori G. Breast cancer as an example of tumour heterogeneity and tumour cell plasticity during malignant progression. Br J Cancer. 2021. https://doi.org/10.1038/s41416-021-01328-7.

    Article  PubMed  PubMed Central  Google Scholar 

  61. Maes K, Mondino A, Lasarte JJ, Agirre X, Vanderkerken K, Prosper F, Breckpot K. Epigenetic modifiers: anti-neoplastic drugs with immunomodulating potential. Front Immunol. 2021;12:652160.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Marshall HT, Djamgoz MB. Immuno-oncology: emerging targets and combination therapies. Front Oncol. 2018;8:315.

    Article  PubMed  PubMed Central  Google Scholar 

  63. Marwitz S, Scheufele S, Perner S, Reck M, Ammerpohl O, Goldmann T. Epigenetic modifications of the immune-checkpoint genes CTLA4 and PDCD1 in non-small cell lung cancer results in increased expression. Clin Epigenetics. 2017;9(1):1–3.

    Google Scholar 

  64. Masili-Oku SM, de Almeida BGL, Bacchi CE, Filassi JR, Baracat EC, Carvalho FM. Lymphocyte-predominant triple-negative breast carcinomas in premenopausal patients: lower expression of basal immunohistochemical markers. Breast. 2017;31:34–9.

    Article  PubMed  Google Scholar 

  65. Matsumoto H, Koo S-L, Dent R, Tan PH, Iqbal J. Role of inflammatory infiltrates in triple negative breast cancer. J Clin Pathol. 2015;68(7):506–10.

    Article  CAS  PubMed  Google Scholar 

  66. McAlpine JN, Porter H, Köbel M, Nelson BH, Prentice LM, Kalloger SE, Shah SP. BRCA1 and BRCA2 mutations correlate with TP53 abnormalities and presence of immune cell infiltrates in ovarian high-grade serous carcinoma. Mod Pathol. 2012;25(5):740–50.

    Article  CAS  PubMed  Google Scholar 

  67. McGuire S. World cancer report 2014. Geneva, Switzerland: World Health Organization, international agency for research on cancer, WHO Press, 2015. Adv Nutr. 2016;7(2):418–419.

  68. Mediratta K, El-Sahli S, D’Costa V, Wang L. Current progresses and challenges of immunotherapy in triple-negative breast cancer. Cancers. 2020;12(12):3529.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Melssen M, Slingluff CL Jr. Vaccines targeting helper T cells for cancer immunotherapy. Curr Opin Immunol. 2017;47:85–92.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Mihic-Probst D, Reinehr M, Dettwiler S, Kolm I, Britschgi C, Kudura K, Rushing EJ. The role of macrophages type 2 and T-regs in immune checkpoint inhibitor related adverse events. Immunobiology. 2020;225(5):152009. https://doi.org/10.1016/j.imbio.2020.152009.

    Article  CAS  PubMed  Google Scholar 

  71. Mirandola L, Pedretti E, Figueroa JA, Chiaramonte R, Colombo M, Chapman C, Nguyen DD. Cancer testis antigen Sperm Protein 17 as a new target for triple negative breast cancer immunotherapy. Oncotarget. 2017;8(43):74378.

    Article  PubMed  PubMed Central  Google Scholar 

  72. Navarrete-Bernal MG, Cervantes-Badillo MG, Martínez-Herrera JF, Lara-Torres CO, Gerson-Cwilich R, Zentella-Dehesa A, Cortés-Morales VA. Biological landscape of triple negative breast cancers expressing CTLA-4. Front Oncol. 2020;10:1206.

    Article  PubMed  PubMed Central  Google Scholar 

  73. Nolan E, Savas P, Policheni AN, Darcy PK, Vaillant F, Mintoff CP, Fox SB. Combined immune checkpoint blockade as a therapeutic strategy for BRCA1-mutated breast cancer. Sci Transl Med. 2017. https://doi.org/10.1126/scitranslmed.aal4922.

    Article  PubMed  PubMed Central  Google Scholar 

  74. Onizuka S, Tawara I, Shimizu J, Sakaguchi S, Fujita T, Nakayama E. Tumor rejection by in vivo administration of anti-CD25 (interleukin-2 receptor α) monoclonal antibody. Can Res. 1999;59(13):3128–33.

    CAS  Google Scholar 

  75. Orillion A, Hashimoto A, Damayanti N, Shen L, Adelaiye-Ogala R, Arisa S, Elzey B. Entinostat neutralizes myeloid-derived suppressor cells and enhances the antitumor effect of PD-1 inhibition in murine models of lung and renal cell carcinoma. Clin Cancer Res. 2017;23(17):5187–201.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Padma VV. An overview of targeted cancer therapy. Biomedicine. 2015;5(4):1–6.

    Article  Google Scholar 

  77. Pai C-CS, Simons DM, Lu X, Evans M, Wei J, Wang Y-H, Chang A. Tumor-conditional anti-CTLA4 uncouples antitumor efficacy from immunotherapy-related toxicity. J Clin Investig. 2019;129(1):349–63.

    Article  PubMed  Google Scholar 

  78. Parry RV, Chemnitz JM, Frauwirth KA, Lanfranco AR, Braunstein I, Kobayashi SV, Riley JL. CTLA-4 and PD-1 receptors inhibit T-cell activation by distinct mechanisms. Mol Cell Biol. 2005;25(21):9543–53.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Piccirillo CA. Regulatory T cells in health and disease. Cytokine. 2008;43(3):395–401.

    Article  CAS  PubMed  Google Scholar 

  80. Plottel CS, Blaser MJ. Microbiome and malignancy. Cell Host Microbe. 2011;10(4):324–35.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Prall F, Dührkop T, Weirich V, Ostwald C, Lenz P, Nizze H, Barten M. Prognostic role of CD8+ tumor-infiltrating lymphocytes in stage III colorectal cancer with and without microsatellite instability. Human Pathol. 2004;35(7):808–16.

    Article  CAS  Google Scholar 

  82. Qu Q, Zhai Z, Xu J, Li S, Chen C, Lu B. IL36 cooperates with Anti-CTLA-4 mAbs to facilitate antitumor immune responses. Front Immunol. 2020;11:634. https://doi.org/10.3389/fimmu.2020.00634.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Qureshi OS, Zheng Y, Nakamura K, Attridge K, Manzotti C, Schmidt EM, Briggs Z. Trans-endocytosis of CD80 and CD86: a molecular basis for the cell-extrinsic function of CTLA-4. Science. 2011;332(6029):600–3.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Relecom A, Merhi M, Inchakalody V, Uddin S, Rinchai D, Bedognetti D, Dermime S. Emerging dynamics pathways of response and resistance to PD-1 and CTLA-4 blockade: tackling uncertainty by confronting complexity. J Exp Clin Cancer Res. 2021;40(1):1–19.

    Article  Google Scholar 

  85. Ribas A. Clinical development of the anti–CTLA-4 antibody tremelimumab. Paper presented at the Seminars in oncology. 2010.

  86. Roca C, Requena C, Sebastián-Pérez V, Malhotra S, Radoux C, Pérez C, Campillo NE. Identification of new allosteric sites and modulators of AChE through computational and experimental tools. J Enzyme Inhib Med Chem. 2018;33(1):1034–47.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Rotte A. Combination of CTLA-4 and PD-1 blockers for treatment of cancer. J Exp Clin Cancer Res. 2019;38:1–12.

    Article  Google Scholar 

  88. Routy B, Gopalakrishnan V, Daillère R, Zitvogel L, Wargo JA, Kroemer G. The gut microbiota influences anticancer immunosurveillance and general health. Nat Rev Clin Oncol. 2018;15(6):382–96.

    Article  CAS  PubMed  Google Scholar 

  89. Rudd CE, Taylor A, Schneider H. CD28 and CTLA-4 coreceptor expression and signal transduction. Immunol Rev. 2009;229(1):12–26.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Salvatori E, Lione L, Compagnone M, Pinto E, Conforti A, Ciliberto G, Palombo F. Neoantigen cancer vaccine augments anti-CTLA-4 efficacy. NPJ Vaccines. 2022;7(1):15.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Santa-Maria CA, Kato T, Park J-H, Flaum LE, Jain S, Tellez C, Uthe R. Durvalumab and tremelimumab in metastatic breast cancer (MBC): Immunotherapy and immunopharmacogenomic dynamics. In: American society of clinical oncology. 2017.

  92. Savas P, Salgado R, Denkert C, Sotiriou C, Darcy PK, Smyth MJ, Loi S. Clinical relevance of host immunity in breast cancer: from TILs to the clinic. Nat Rev Clin Oncol. 2016;13(4):228–41.

    Article  CAS  PubMed  Google Scholar 

  93. Schwarz C, Unger L, Mahr B, Aumayr K, Regele H, Farkas A, Wekerle T. The immunosuppressive effect of CTLA4 immunoglobulin is dependent on regulatory T cells at low but not high doses. Am J Transplant. 2016;16(12):3404–15.

    Article  CAS  PubMed  Google Scholar 

  94. Selby MJ, Engelhardt JJ, Quigley M, Henning KA, Chen T, Srinivasan M, Korman AJ. Anti-CTLA-4 antibodies of IgG2a isotype enhance antitumor activity through reduction of intratumoral regulatory T cells. Cancer Immunol Res. 2013;1(1):32–42.

    Article  CAS  PubMed  Google Scholar 

  95. Shimizu J, Yamazaki S, Sakaguchi S. Induction of tumor immunity by removing CD25+ CD4+ T cells: a common basis between tumor immunity and autoimmunity. J Immunol. 1999;163(10):5211–8.

    Article  CAS  PubMed  Google Scholar 

  96. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2019. CA Cancer J Clin. 2019;69(1):7–34.

    Article  PubMed  Google Scholar 

  97. Simpson TR, Li F, Montalvo-Ortiz W, Sepulveda MA, Bergerhoff K, Arce F, Wolchok JD. Fc-dependent depletion of tumor-infiltrating regulatory T cells co-defines the efficacy of anti–CTLA-4 therapy against melanoma. J Exp Med. 2013;210(9):1695–710.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. Siurala M, Havunen R, Saha D, Lumen D, Airaksinen AJ, Tähtinen S, Vähä-Koskela M. Adenoviral delivery of tumor necrosis factor-α and interleukin-2 enables successful adoptive cell therapy of immunosuppressive melanoma. Mol Ther. 2016;24(8):1435–43.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. Sivan A, Corrales L, Hubert N, Williams JB, Aquino-Michaels K, Earley ZM, Alegre M-L. Commensal Bifidobacterium promotes antitumor immunity and facilitates anti–PD-L1 efficacy. Science. 2015;350(6264):1084–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. Smith WM, Purvis IJ, Bomstad CN, Labak CM, Velpula KK, Tsung AJ, Asuthkar S. Therapeutic targeting of immune checkpoints with small molecule inhibitors. Am J Transl Res. 2019;11(2):529.

    CAS  PubMed  PubMed Central  Google Scholar 

  101. Snyder A, Makarov V, Merghoub T, Yuan J, Zaretsky JM, Desrichard A, Ho TS. Genetic basis for clinical response to CTLA-4 blockade in melanoma. N Engl J Med. 2014;371(23):2189–99.

    Article  PubMed  PubMed Central  Google Scholar 

  102. Sobhani N, Tardiel-Cyril DR, Davtyan A, Generali D, Roudi R, Li Y. CTLA-4 in regulatory T cells for cancer immunotherapy. Cancers. 2021;13(6):1440.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. Son CH, Bae J, Lee HR, Yang K, Park YS. Enhancement of antitumor immunity by combination of anti-CTLA-4 antibody and radioimmunotherapy through the suppression of Tregs. Oncol Lett. 2017;13(5):3781–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. Song Y, Lai L, Chong Z, He J, Zhang Y, Xue Y, Chen L. E3 ligase FBXW7 is critical for RIG-I stabilization during antiviral responses. Nat Commun. 2017;8(1):1–14.

    Article  Google Scholar 

  105. Stanton SE, Adams S, Disis ML. Variation in the incidence and magnitude of tumor-infiltrating lymphocytes in breast cancer subtypes: a systematic review. JAMA Oncol. 2016;2(10):1354–60. https://jamanetwork.com/journals/jamaoncology/article-abstract/2529697.

  106. Sun Y, Meyers BA, Czako B, Leonard P, Mseeh F, Harris AL, Cross JB. Allosteric SHP2 Inhibitor IACS-13909, overcomes EGFR-Dependent and EGFR-independent resistance mechanisms toward osimertinibtargeting SHP2 to overcome osimertinib resistance. Cancer Res. 2020;80(21):4840–53.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. Tabana Y, Moon TC, Siraki A, Elahi S, Barakat K. Reversing T-cell exhaustion in immunotherapy: a review on current approaches and limitations. Expert Opin Ther Targets. 2021;25(5):347–63.

    Article  CAS  PubMed  Google Scholar 

  108. Tanaka A, Sakaguchi S. Regulatory T cells in cancer immunotherapy. Cell Res. 2017;27(1):109–18.

    Article  CAS  PubMed  Google Scholar 

  109. Tang F, Du X, Liu M, Zheng P, Liu Y. Anti-CTLA-4 antibodies in cancer immunotherapy: selective depletion of intratumoral regulatory T cells or checkpoint blockade? Cell Biosci. 2018;8(1):1–3.

    Article  Google Scholar 

  110. Taylor NA, Vick SC, Iglesia MD, Brickey WJ, Midkiff BR, McKinnon KP, Parker JS. Treg depletion potentiates checkpoint inhibition in claudin-low breast cancer. J Clin Invest. 2017;127(9):3472–83. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5669567/pdf/jci-127-90499.pdf.

  111. Vargas FA, Furness AJ, Litchfield K, Joshi K, Rosenthal R, Ghorani E, Roddie C. Fc effector function contributes to the activity of human anti-CTLA-4 antibodies. Cancer Cell. 2018;33(4):649–63.e644.

    Article  Google Scholar 

  112. Vétizou M, Pitt JM, Daillère R, Lepage P, Waldschmitt N, Flament C, Duong CP. Anticancer immunotherapy by CTLA-4 blockade relies on the gut microbiota. Science. 2015;350(6264):1079–84.

    Article  PubMed  PubMed Central  Google Scholar 

  113. Vockley CM, Barrera A, Reddy TE. Decoding the role of regulatory element polymorphisms in complex disease. Curr Opin Genet Dev. 2017;43:38–45.

    Article  CAS  PubMed  Google Scholar 

  114. Wang DY, Salem J-E, Cohen JV, Chandra S, Menzer C, Ye F, Ha L. Fatal toxic effects associated with immune checkpoint inhibitors: a systematic review and meta-analysis. JAMA Oncol. 2018;4(12):1721–8.

    Article  PubMed  PubMed Central  Google Scholar 

  115. Watanabe T, Ishino T, Ueda Y, Nagasaki J, Sadahira T, Dansako H, Togashi Y. Activated CTLA-4-independent immunosuppression of Treg cells disturbs CTLA-4 blockade-mediated antitumor immunity. Cancer Sci. 2023;114(5):1859.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  116. Weber JS, O’Day S, Urba W, Powderly J, Nichol G, Yellin M, Hersh E. Phase I/II study of ipilimumab for patients with metastatic melanoma. J Clin Oncol. 2008;26(36):5950–6.

    Article  CAS  PubMed  Google Scholar 

  117. Wen WX, Leong C-O. Association of BRCA1-and BRCA2-deficiency with mutation burden, expression of PD-L1/PD-1, immune infiltrates, and T cell-inflamed signature in breast cancer. PLoS One. 2019;14(4):e0215381.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  118. Xiong H, Mittman S, Rodriguez R, Moskalenko M, Pacheco-Sanchez P, Yang Y, Cubas R. Anti–PD-L1 treatment results in functional remodeling of the macrophage compartment. Can Res. 2019;79(7):1493–506.

    Article  CAS  Google Scholar 

  119. Yan C, Yang J, Saleh N, Chen S-C, Ayers GD, Abramson VG, Richmond A. Inhibition of the PI3K/mTOR pathway in breast cancer to enhance response to immune checkpoint inhibitors in breast cancer. Int J Mol Sci. 2021;22(10):5207.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  120. Yang X-P, Jiang K, Hirahara K, Vahedi G, Afzali B, Sciume G, Kanno Y. EZH2 is crucial for both differentiation of regulatory T cells and T effector cell expansion. Sci Rep. 2015;5(1):10643.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  121. Zhang H, Xie W, Zhang Y, Dong X, Liu C, Yi J, Wang H. Oncolytic adenoviruses synergistically enhance anti-PD-L1 and anti-CTLA-4 immunotherapy by modulating the tumour microenvironment in a 4T1 orthotopic mouse model. Cancer Gene Ther. 2021. https://doi.org/10.1038/s41417-021-00389-3.

    Article  PubMed  PubMed Central  Google Scholar 

  122. Zhang Y, Du X, Liu M, Tang F, Zhang P, Ai C, Devenport M. Hijacking antibody-induced CTLA-4 lysosomal degradation for safer and more effective cancer immunotherapy. Cell Res. 2019;29(8):609–27.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  123. Zhu Y, Zhu X, Tang C, Guan X, Zhang W. Progress and challenges of immunotherapy in triple-negative breast cancer. Biochimica et Biophysica Acta (BBA) Rev Cancer. 2021;1876(2):188593.

    Article  CAS  Google Scholar 

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Funding

This work was supported by Alberta Cancer foundation, Natural Sciences and engineering research council of Canada and Kidney foundation.

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Authors and Affiliations

  1. Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, Canada

    Maryam Jama, Yasser Tabana & Khaled H. Barakat

  2. Li Ka Shing Institute of Virology, University of Alberta, Edmonton, Canada

    Khaled H. Barakat

  3. Faculty of Medicine and Dentistry, University of Alberta, Edmonton, Canada

    Yasser Tabana

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  1. Maryam Jama
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MJ and YT collected the data and wrote the initial draft. KB edited and reviewed the manuscript, and provided supervsion. The author (YT) would like to thank Alberta Innovates for providing the Postdoctoral Recruitment Fellowship.

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Correspondence to Khaled H. Barakat.

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Jama, M., Tabana, Y. & Barakat, K.H. Targeting cytotoxic lymphocyte antigen 4 (CTLA-4) in breast cancer. Eur J Med Res 29, 353 (2024). https://doi.org/10.1186/s40001-024-01901-9

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  • DOI: https://doi.org/10.1186/s40001-024-01901-9

European Journal of Medical Research

ISSN: 2047-783X

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