Description

Intra-tumoral PD-1^hi T cells represent a unique subset of human exhausted lymphocytes with a distinct molecular, functional and metabolic profile

D.S. Thommen^1,2*, 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

^*Corresponding author

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-1^hi and PD-1^int 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-1^hi, PD-1^int and PD-1^neg 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-1^int T cells are largely similar to PD-1^neg T cells, PD-1^hi 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-1^hi TILs, they retained an underlying susceptibility to immunosuppressive factors in the tumor microenvironment.

Conclusion: PD-1^hi T cells represent a unique subset of dysfunctional lymphocytes. The identification of therapeutic strategies that are able to restore classical effector functions in PD-1^hi T cells might greatly improve clinical responses to cancer immunotherapies.