UCSF

Immune checkpoint blockade (ICB) therapies have led to durable tumor responses in patients across cancer types. However, a significant proportion of patients still do not benefit from ICB. CD8 T cell exhaustion is a major barrier to ICB efficacy. In contrast to acute infection where CD8 T cells form potent effector and memory cells, tumor-specific CD8 T cells instead become exhausted or dysfunctional, progressively losing proliferative capacity, effector function, and cytotoxicity. Progenitor exhausted CD8 T cells (Tpex) are the primary subset of tumor-reactive CD8 T cells that respond to ICB, undergoing proliferation and subsequent differentiation into terminally exhausted cells (Tex-term). Although Tex-term increase in abundance after ICB treatment, they remain hypofunctional. Therefore, a major goal in the field is to promote the differentiation of tumor-reactive CD8 T cells into highly functional and cytotoxic effector-like cells. Here, we investigated two strategies for driving effector-like CD8 T cell differentiation in cancer. First, we identified the cytokine IL-7 as a key signal that induces Tpex proliferation and skews Tpex differentiation into unique effector-like cells with superior cytokine production and cytotoxicity. Furthermore, we determined that agonistic CD40 antibodies (CD40a) drive the expansion of tumor-reactive CD8 T cells with a KLRG1+ effector-like phenotype. However, CD40a also seems to induce non-specific bystander CD8 T cell activation and expansion. Taken together, these studies advance our understanding of how cell-extrinsic signals can promote effector-like CD8 T differentiation in cancer.