CD25 identifies a subset of CD4⁺FoxP3⁻ TIL that are exhausted yet prognostically favorable in human ovarian cancer

• Published in: Cancer immunology research Vol. 3; no. 3; p. 245
• Main Authors: deLeeuw, Ronald J, Kroeger, David R, Kost, Sara E, Chang, Pheh-Ping, Webb, John R, Nelson, Brad H
• Format: Journal Article
• Language: English
• Published: United States 01.03.2015
• Subjects: Adult; Aged; Aged, 80 and over; CD8-Positive T-Lymphocytes - immunology; Cytokines - immunology; Female; Flow Cytometry; Forkhead Transcription Factors - metabolism; Humans; Interleukin-2 Receptor alpha Subunit - metabolism; Lymphocytes, Tumor-Infiltrating - immunology; Middle Aged; Ovarian Neoplasms - immunology; Prognosis; T-Lymphocytes, Regulatory - immunology
• ISSN: 2326-6074
• DOI: 10.1158/2326-6066.CIR-14-0146

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 (IFNγ, TNFα, 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.