Prognostic Implications of Immune Infiltrates in the Breast Cancer Microenvironment: The Role of Expressions of CTLA-4, PD-1, and LAG-3

The assessment of immune infiltrate in invasive breast carcinomas (IBCs), most commonly referred to as tumor infiltrating lymphocytes (TILs), is gaining importance in the current quest for optimal biomarker selection and prediction of prognosis. In this study, the impact of intensity of TILs and expressions of cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), programmed cell death-1 (PD-1), and lymphocyte activation gene 3 (LAG-3) in a group of breast carcinomas with regards to the prognosis and conventional pathologic parameters was scrutinized. For this purpose, 238 patients with IBCs containing different proportions of TILs were included in the study. IBCs with higher proportion of TILs were usually grade III carcinomas and correlated with poor prognostic features like receptor negativity, nonluminal intrinsic subtype (P<0.001). Similarly, PD-1 and LAG-3 positivity in immune cells (IC) were more likely to be positive in grade III IBC cases (P=0.004). In addition, PD-1 positivity in IC was more frequent in estrogen receptor-negative tumors (P=0.011) whereas LAG-3 positivity increased in large sized, estrogen receptor and progesterone receptor-negative tumors (P=0.050, 0.023, 0.04, respectively). CTLA-4 positivity in IC was more frequent in large-sized tumors (P=0.040). These 3 markers were also significantly associated with one another and also with the amount of TILs. In survival analysis, cases with prominent-TILs especially displaying CTLA-4, PD-1, and LAG-3 positivity appeared to have longer disease-free and overall survival (CTLA-4: P=0.027, P=0.024; PD-1: P=0.030, P=0.026; LAG-3: P=0.006, P=0.012, respectively). We conclude that the high proportion of TILs and as well as high expression of CTLA-4, PD-1, and LAG-3 in TILs have positively contributed to the outcome despite their correlation with poor conventional pathologic features. We suggest that these 3 immune markers can be used for the determination of proper treatment as well as prediction of prognosis in IBCs with TILs.