OX40 agonism enhances PD-L1 checkpoint blockade by shifting the cytotoxic T cell differentiation spectrum

Sluis, T.C. van der; Beyrend, G.; Gracht, E.T.I.V.; Abdelaal, T.; Jochems, S.P.; Belderbos, R.A.; Wesselink, T.H.; Duikeren, S.V.; Haften, F.J.V.; Redeker, A.; Ouboter, L.F.; Nejad, E.B.; Camps, M.; Franken, K.L.M.C.; Linssen, M.M.; Hohenstein, P.; Miranda, N.F.C.C.D.; Mei, H.L.; Bins, A.D.; Haanen, J.B.A.G.; Aerts, J.G.; Ossendorp, F.; Arens, R.

doi:doi:10.1016/j.xcrm.2023.100939

Immune checkpoint therapy (ICT) has the power to eradicate cancer, but the mechanisms that determine effective therapy-induced immune responses are not fully understood. Here, using high-dimensional sin-gle-cell profiling, we interrogate whether the landscape of T cell states in the peripheral blood predict re-sponses to combinatorial targeting of the OX40 costimulatory and PD-1 inhibitory pathways. Single-cell RNA sequencing and mass cytometry expose systemic and dynamic activation states of therapy-responsive CD4+ and CD8+ T cells in tumor-bearing mice with expression of distinct natural killer (NK) cell receptors, granzymes, and chemokines/chemokine receptors. Moreover, similar NK cell receptor-expressing CD8+ T cells are also detected in the blood of immunotherapy-responsive cancer patients. Targeting the NK cell and chemokine receptors in tumor-bearing mice shows the functional importance of these receptors for ther-apy-induced anti-tumor immunity. These findings provide a...Show moreImmune checkpoint therapy (ICT) has the power to eradicate cancer, but the mechanisms that determine effective therapy-induced immune responses are not fully understood. Here, using high-dimensional sin-gle-cell profiling, we interrogate whether the landscape of T cell states in the peripheral blood predict re-sponses to combinatorial targeting of the OX40 costimulatory and PD-1 inhibitory pathways. Single-cell RNA sequencing and mass cytometry expose systemic and dynamic activation states of therapy-responsive CD4+ and CD8+ T cells in tumor-bearing mice with expression of distinct natural killer (NK) cell receptors, granzymes, and chemokines/chemokine receptors. Moreover, similar NK cell receptor-expressing CD8+ T cells are also detected in the blood of immunotherapy-responsive cancer patients. Targeting the NK cell and chemokine receptors in tumor-bearing mice shows the functional importance of these receptors for ther-apy-induced anti-tumor immunity. These findings provide a better understanding of ICT and highlight the use and targeting of dynamic biomarkers on T cells to improve cancer immunotherapy.Show less

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OX40 agonism enhances PD-L1 checkpoint blockade by shifting the cytotoxic T cell differentiation spectrum