title: CD25 identifies a subset of CD4⁺FoxP3⁻ TIL that are exhausted yet prognostically favorable in human ovarian cancer.
abstract: 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.
authors.affiliation: Deeley Research Centre, BC Cancer Agency, Victoria, British Columbia, Canada. Department of Biochemistry and Microbiology, University of Victoria, Victoria, British Columbia, Canada.
authors.forename: Ronald J
authors.initials: RJ
authors.lastname: deLeeuw
authors.affiliation: Deeley Research Centre, BC Cancer Agency, Victoria, British Columbia, Canada.
authors.forename: David R
authors.initials: DR
authors.lastname: Kroeger
authors.affiliation: Deeley Research Centre, BC Cancer Agency, Victoria, British Columbia, Canada. Department of Biochemistry and Microbiology, University of Victoria, Victoria, British Columbia, Canada.
authors.forename: Sara E
authors.initials: SE
authors.lastname: Kost
authors.affiliation: Deeley Research Centre, BC Cancer Agency, Victoria, British Columbia, Canada.
authors.forename: Pheh-Ping
authors.initials: PP
authors.lastname: Chang
authors.affiliation: Deeley Research Centre, BC Cancer Agency, Victoria, British Columbia, Canada. Department of Biochemistry and Microbiology, University of Victoria, Victoria, British Columbia, Canada.
authors.forename: John R
authors.initials: JR
authors.lastname: Webb
authors.affiliation: Deeley Research Centre, BC Cancer Agency, Victoria, British Columbia, Canada. Department of Biochemistry and Microbiology, University of Victoria, Victoria, British Columbia, Canada. Department of Medical Genetics, University of British Columbia, Vancouver, British Columbia, Canada. bnelson@bccrc.ca.
authors.forename: Brad H
authors.initials: BH
authors.lastname: Nelson
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D016207:Cytokines / Q000276:immunology; D005260:Female; D005434:Flow Cytometry; D051858:Forkhead Transcription Factors / Q000378:metabolism*; D006801:Humans; D053645:Interleukin-2 Receptor alpha Subunit / Q000378:metabolism*; D016246:Lymphocytes, Tumor-Infiltrating / Q000276:immunology*; D008875:Middle Aged; D010051:Ovarian Neoplasms / Q000276:immunology*; D011379:Prognosis; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*
chemical_list: D016207:Cytokines; C418974:FOXP3 protein, human; D051858:Forkhead Transcription Factors; C508017:IL2RA protein, human; D053645:Interleukin-2 Receptor alpha Subunit