Abstract

T-cell exhaustion plays an important part in the impairment of anti-tumor immune responses observed in cancer patients. T-cell exhaustion is a differentiation stage characterized by progressive loss of effector functions and expression of multiple inhibitory receptors, usually observed in aging and chronic inflammatory contexts such as cancer and persistent infections. Antibodies targeting inhibitory receptors have enabled considerable advances in cancer treatment; however, these treatments are not always effective. Our recent findings suggest that age-related inflammation (like exposure to pro-inflammatory cytokines such as type I interferons (IFN) and TNF-α) promotes the development of T-cell exhaustion via decreased expression of a transcription factor called Foxo1.

In the tumor microenvironment, pro-inflammatory cytokines play a paradoxical role: while they support immune activation, they can also exert either direct or indirect pro-tumoral effects.

My project aims to determine whether pro-inflammatory cytokines and Foxo1 downregulation could also be involved in T-cell exhaustion in the tumor microenvironment, as well as the broader impact of inflammatory cytokines on tumor growth. We identified Foxo1 downregulation in tumor-infiltrating lymphocytes (TILs) from various mouse tumor models (transplanted, induced and spontaneous). Foxo1 downregulation is associated with increased expression of several exhaustion markers in the MC38 tumor model. Furthermore, transcriptomic, epigenetic and phenotypic analyses of Foxo1-deficient naive CD4 T cells revealed a differentiation program oriented towards exhaustion, suggesting that Foxo1 loss predisposes T cells to this dysfunctional stage. Additionally, both genetic and pharmacological inhibition of Foxo1 in T cells enhances the expression of some exhaustion markers after 4 days of in vitro activation.

We also showed that, both in vitro and in vivo, type I IFNs and TNFα synergistically act to suppress Foxo1 expression in T cells, thereby reinforcing T-cell exhaustion in tumor context.

In a second study, we investigated the impact of TNFα on tumor growth. Deletion of the TNFα gene in two murine tumor cell lines (MC38 and EL4) led to complete tumor rejection in vivo in the absence of TNFα production by either host and tumor cells. This rejection is T-cell dependent and induces a robust memory T cell response, protecting the mice against a second tumor challenge. Characterization of the tumor microenvironment in the absence of TNFα will help to identify the involved immune mechanisms.

In conclusion, our findings highlight a synergistic effect of type I IFNs and TNFα in driving T-cell exhaustion via Foxo1 downregulation, thereby contributing to the failure of anti-tumor immune responses. They also show a major pro-tumoral role of TNFα.