Expression of immune checkpoint regulators, cytotoxic T lymphocyte antigen 4 (CTLA-4) and programmed death-ligand 1 (PD-L1), in female breast carcinomas

Abstract

BackgroundImmune checkpoint regulators, cytotoxic T lymphocyte antigen 4 (CTLA-4) and the programmed cell death protein-1/programmed death-ligand 1 (PD-1/PD-L1) have emerged as promising new targets for cancer therapeutics. While tumor expression of PD-L1 has been shown to have objective responses to anti-PD-L1 immunotherapies, the clinical implications of CTLA-4 expression in tumor cells or immune cells in the tumor microenvironment is still controversial. We investigated the expression of CTLA-4 and PD-L1 in human breast tumors and provided a scoring system for the systematic evaluation of CTLA-4 staining.MethodsImmunohistochemical staining for PD-L1 and CTLA-4 expression was performed on a tissue microarray of 102 cores, which included normal and neoplastic breast tissues. Neoplastic cores were divided into four groups: Ductal carcinoma in situ (DCIS), invasive ductal carcinoma (IDC), invasive lobular carcinoma (ILC) and invasive tubular carcinoma (ITC). PD-L1 and CTLA-4 expressions were scored based on a system which accounted for the percentage and intensity of positivity and results provided in conjunction with available clinical and demographic data.ResultsOverall, CTLA-4 was over-expressed in 49 of 93 (52.7%) breast tumors. Subcategorically, CTLA-4 was positive in 3 of 8 (37.5%) ductal carcinoma in situ, 40 of 73 (55%) of invasive ductal carcinomas, 4 of 10 (40%) of invasive lobular carcinomas and 2 of 2 (100%) of invasive tubular carcinomas. All 6 normal breast tissues were interpreted as negative for CTLA-4 staining. Only 4.1% of the invasive ductal carcinomas were positive for PD-L1 reactivity and the remaining carcinomas stained negative.ConclusionsThis study shows a significant overexpression of CTLA-4 in >50% of breast carcinomas with no such overexpression of CTLA-4 in benign breast tissues. PDL-1 staining is seen in only a small number of invasive ductal carcinomas (4.1%). These findings suggest the need for further investigation of anti-CTLA-4 and anti-PD-L1 immunotherapies and their efficacy in the treatment of breast carcinomas with overexpression of these immune modulators. In addition, the proposed scoring system will facilitate a more systematic correlation between tumor reactivity and clinical outcome which can be applied to all intracytoplasmic tumor markers.

Beyond PD-1/PD-L1 Inhibition: What the Future Holds for Breast Cancer Immunotherapy

“…In metastatic BC (MBC), TIL enumeration has not proven to be as successful [5], since TIL counts have been shown to be lower in metastatic sites compared to the primary tumor [6]. On the other hand, Programmed Cell Death Protein 1 (PD-1) and its ligand PD-L1, as well as cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), have been extensively evaluated as putative markers of response to immunotherapy with PD-1/PD-L1 and CTLA-4 blockade, respectively [7,8]. Although data stemming from randomized clinical trials in various human cancers are conflicting, in MBC only one phase 3 trial has been reported demonstrating increased benefit from the combination of atezolizumab and nab-paclitaxel compared to nab-paclitaxel alone in patients whose tumors expressed PD-L1 [9].…”

Biological Landscape of Triple Negative Breast Cancers Expressing CTLA-4

“…Thereafter, the expression of CTLA-4 at protein and mRNA levels was demonstrated in breast cancer (60). More recently, CTLA-4 has been reported to be over-expressed in a high proportion of breast cancer samples (18). In contrast with former reports, we exclusively focused our study on the expression of CTLA-4 in TNBC.…”

“…The expression of CTLA-4 in various tumor types and cancer cell lines has been previously described (14)(15)(16)(17). It has also been reported that expression of CTLA-4 occurs in around 50% of breast carcinomas, but not in normal breast tissues (18). However, evidence describing CTLA-4 signal transduction pathways in TNBC cells, and the potential effects of its modulation, is still limited.…”

Association between αβ and γδ T‑cell subsets and clinicopathological characteristics in patients with breast cancer

“…CD3 + T cells are the main active cells in cellular immunity, representing the proportion of mature lymphocytes among the total T cells. CD4 + T cells are helper T cells, whereas CD8 + T cells exert both cytotoxic and immunosuppressive effects, and the CD4 + /CD8 + ratio reflects the status of cellular immunity ( 8 ). The results of the present study demonstrated that, due to the presence of BC target cells, the CD3 + , CD4 + and γδ Τ-cell counts and the CD4 + /CD8 + ratio in the peripheral blood of the patients prior to surgery were significantly lower compared with those in healthy volunteers.…”