Cancer induced CD8 T cell dysfunction: Beyond inhibitory receptors

Ludovic Martinet (Centre de Recherches en Cancérologie de Toulouse)

15 June 2023

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12:00 - 13:00
Conference room Rosalind Franklin
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Although immune checkpoint blockade (ICB) such as anti-PD-1 has represented a turning point in cancer care, clinical responses are not observed in the majority of cancer patients. The mechanisms underlying this lack of responsiveness are still poorly understood and finding additional signals that regulate CD8+ T cell anti-tumor functions has become a major priority. While most studies focus on inhibitory receptors, signals transmitted through activating receptors also critically impact CD8+ T cell cancer immune surveillance and ICB efficacy. Indeed, we recently discovered that the loss of the activating receptor CD226 restrains CD8+ T cell functions and the therapeutic efficacy of cancer immunotherapy (Weulersse et al, Immunity. 2020). More recently, we focused on CD137 (4-1BB) activating receptor, an enigmatic yet, promising target for immunotherapy. Using T cell-specific CD137-deficient mice and agonists antibodies, we found that CD137 modulates tumor infiltration of CD8+ exhausted T (Tex) cells. We demonstrated that T cell-intrinsic, TCR-independent, CD137 signaling involving the RelA and cRel NF-kB subunits induced the proliferation and the terminal differentiation of CD8+ T cells already committed into Tex cell program. Indeed, CD137 was specifically expressed by Tex cells and induced the Tox-dependent chromatin remodeling and expression of PD1, Lag-3 and Tim-3 immune checkpoints. Manipulating Tex subsets represents one of the most promising anti-tumor strategies. Yet, pre-existing tumor-specific T cells may have limited reinvigoration capacity, and the T cell response to checkpoint blockade rather derives from a distinct repertoire of T cell clones that may have recently entered the tumor. In this context, Tex cell expansion by anti-CD137 agonists may useful and could improve ICB efficacy as evidenced by the ability of CD137 agonists to improve anti-PD1 efficacy in our pre-clinical mouse models.

Invited by Sylvaine You

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