Liu et al. showed that Tim-3+ Tregs in TILs from head and neck squamous cell carcinomas were more suppressive in vitro than their Tim-3- counterparts, and they aimed to understand the mechanism. Tim-3+ Tregs expressed higher levels of co-inhibitory molecules (PD-1 and CTLA-4), granzyme B (but not higher IL-10 or LAP), and IFN-γ receptor. In vitro, IFN-γ or anti-PD-1 treatment reduced Tim-3+ Treg suppressive activity. After five treatments in an in vivo murine model, anti-PD-1 treatment decreased Tim-3 expression, suggesting a possible contribution of Treg suppression to anti-PD-1 therapy.
PURPOSE: Regulatory T (Treg) cells are important suppressive cells among tumor infiltrating lymphocytes (TIL). Treg express the well-known immune checkpoint receptor PD-1, which is reported to mark "exhausted" Treg with lower suppressive function. T cell immunoglobulin mucin (Tim)-3, a negative regulator of Th1 immunity, is expressed by a sizeable fraction of TIL Tregs, but the functional status of Tim-3+ Tregs remains unclear. EXPERIMENTAL DESIGN: CD4+CTLA-4+CD25high Treg were sorted from freshly excised head and neck squamous cell carcinoma (HNSCC) TIL based on Tim-3 expression. Functional and phenotypic features of these Tim-3+ and Tim-3- TIL Tregs were tested by in vitro suppression assays and multi-color flow cytometry. Gene expression profiling and NanoString analysis of Tim-3+ TIL Treg were performed. A murine HNSCC tumor model was used to test the effect of anti-PD-1 immunotherapy on Tim-3+ Treg. Results: Despite high PD-1 expression, Tim-3+ TIL Treg displayed a greater capacity to inhibit naive T cell proliferation than Tim-3- Treg. Tim-3+ Treg from human HNSCC TIL also displayed an effector-like phenotype, with more robust expression of CTLA-4, PD-1, CD39 and IFN-gamma receptor. Exogenous IFN-gamma treatment could partially reverse the suppressive function of Tim-3+ TIL Treg. Anti-PD-1 immunotherapy downregulated Tim-3 expression on Tregs isolated from murine HNSCC tumors, and this treatment reversed the suppressive function of HNSCC TIL Tregs. CONCLUSIONS: Tim-3+ Treg are functionally and phenotypically distinct in HNSCC TIL, and are highly effective at inhibiting T cell proliferation despite high PD-1 expression. IFN-gamma induced by anti-PD-1 immunotherapy may be beneficial by reversing Tim-3+ Treg suppression.
Author Info: (1) Oncology, Shanghai Tenth People's Hospital, Tongji University. (2) Department of Otolaryngology, University of Pittsburgh. (3) School of Medicine, Tsinghua University. (4) Scho
Author Info: (1) Oncology, Shanghai Tenth People's Hospital, Tongji University. (2) Department of Otolaryngology, University of Pittsburgh. (3) School of Medicine, Tsinghua University. (4) School of Medicine, Tsinghua University. (5) University of Pittsburgh, Pittsburgh. (6) Department of Otolaryngology, University of Pittsburgh. (7) Department of Immunology, University of Pittsburgh. (8) Department of immunology, University of Pittsburgh. (9) Cancer Immunology Program, University of Pittsburgh Cancer Institute ferrrl@upmc.edu.
