Intra-tumoral PD-1hi T cells represent a unique subset of human exhausted lymphocytes with a distinct molecular, functional and metabolic profile
D.S. Thommen1,2*, A. Roller3, P. Herzig1, M. Trefny1, F. Uhlenbrock1, W. Moersig4, D. Lardinois4, P.C. Ho5, C.Klein6, V. Karanikas6, T.N. Schumacher2, A. Zippelius1
1Department of Biomedicine, University Hospital Basel, Switzerland; 2Division of Immunology, NKI, Amsterdam, The Netherlands; 3Roche pRED, Roche Innovation Center Basel, Switzerland
4Department of Surgery, University Hospital Basel, Switzerland; 5University of Lausanne, Ludwig Center for Cancer Research, Epalinges, Switzerland; 6Roche pRED, Roche Innovation Centre Zurich, Switzerland
Background: Despite encouraging antitumor activity of antibodies targeting the PD-1:PD-L1 axis in multiple cancers, to date only a minority of patients achieve long-term benefit. Previous studies in murine chronic infection models have identified two distinct T cell populations, PD-1hi and PD-1int that respond differently to PD-1 blockade. However, it is unknown whether a similar heterogeneity in PD-1 expression also exists in human cancer.
Methods: We performed extensive profiling of sorted PD-1hi, PD-1int and PD-1neg CD8+ T cell subsets from freshly resected surgical samples of patients with non-small cell lung cancer.
Results: We found that intra-tumoral PD-1+ cells comprise two populations that are clearly distinct from each other. Whereas PD-1int T cells are largely similar to PD-1neg T cells, PD-1hi T cells comprise a highly clonal subset that shows a markedly different phenotypic, metabolic and transcriptional profile as well as completely altered cytokine expression. Although short-term ex vivo culture in high-dose IL-2 could at least temporarily restore functionality in PD-1hi TILs, they retained an underlying susceptibility to immunosuppressive factors in the tumor microenvironment.
Conclusion: PD-1hi T cells represent a unique subset of dysfunctional lymphocytes. The identification of therapeutic strategies that are able to restore classical effector functions in PD-1hi T cells might greatly improve clinical responses to cancer immunotherapies.
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