CD25 Identifies a Subset of CD4+FoxP3- TIL That Are Exhausted Yet Prognostically Favorable in Human Ovarian Cancer

CD25, the alpha subunit of the IL2 receptor, is a canonical marker of regulatory T cells (Treg) and hence has been implicated in immune suppression in cancer. However, CD25 is also required for optimal expansion and activity of effector T cells in peripheral tissues. Thus, we hypothesized that CD25, in addition to demarcating Tregs, might identify effector T cells in cancer. To investigate this possibility, we used multiparameter flow cytometry and IHC to analyze tumor-infiltrating lymphocytes (TIL) in primary high-grade serous carcinomas, the most common and fatal subtype of ovarian cancer. CD25 was expressed primarily by CD4(+) TIL, with negligible expression by CD8(+) TIL. In addition to conventional CD25(+)FoxP3(+) Tregs, we identified a subset of CD25(+)FoxP3(-) T cells that comprised up to 13% of CD4(+) TIL. In tumors with CD8(+) TIL, CD25(+)FoxP3(-) T cells showed a strong positive association with patient survival (HR, 0.56; P = 0.02), which exceeded the negative effect of Tregs (HR, 1.55; P = 0.09). Among CD4(+) TIL subsets, CD25(+)FoxP3(-) cells expressed the highest levels of PD-1. Moreover, after in vitro stimulation, they failed to produce common T-helper cytokines (IFN gamma, TNF alpha, IL2, IL4, IL10, or IL17A), suggesting that they were functionally exhausted. In contrast, the more abundant CD25(-)FoxP3(-) subset of CD4(+) TIL expressed low levels of PD-1 and produced T-helper 1 cytokines, yet conferred no prognostic benefit. Thus, CD25 identifies a subset of CD4(+)FoxP3(-) TIL that, despite being exhausted at diagnosis, have a strong, positive association with patient survival and warrant consideration as effector T cells for immunotherapy. (C) 2014 AACR.