CD4 helper programs that regulate intratumoral immunity

SUMMARY Immunotherapies have changed the landscape of cancer treatment, but remain mostly focused on CD8 T cells. In liver cancer patients, we found that in addition to expansion of PD-1+ effector- like CD8 T cells, expansion of CD4 T cells with similarities to follicular helper cells (Tfh) was associated with response to PD-1 targeted therapy. Tfh-like were found in close association to progenitor exhausted CD8 T cells and activated dendritic cells. Overall, our data in patients suggest that CD4-helpers may promote intratumoral differentiation of progenitor exhausted CD8 T cells into effector-like CD8 T cells that control tumor growth. The role of CD4-help in priming is well established, but the role of conventional CD4 T cells in sustaining effective anti-tumor responses and contributing to PD-1 targeted therapy needs to be better understood. In this study, using an autochthonous immunogenic mouse model of liver cancer, we propose to define the key cell-intrinsic features and cell interactions of anti-tumor CD4 T cells that promote anti-tumor immunity and enhance responses to PD-1 targeted therapy. In Aim 1, we will study transcriptional programs and secreted factors in CD4-helper T cells that aid anti-tumor immune responses. In Aim2, we will address how PD-1 signaling modulates tumor-specific CD4 T cells. In Aim3, we will identify CD4-helper interacting partners, and how CD4-help affects cell interactions of tumor-specific CD8 T cells. Given that the frequency Tfh-like in patients' tumors was corelated with plasma cells, we will specifically address the contribution of B cells (and the role of antibodies) in modulating anti-tumor responses, including phenotype of tumor-specific CD4 T cells. Finally, we will address the role of dendritic cells interactions with CD4 T cells, beyond T cell priming, to assess whether CD4-licensing is required for effective response to PD-1 targeted immunotherapy. Understanding what are the key interactions and signals that promote persistent T cell responses in tissues is critical to improve therapies for conditions mediated by chronic T cell stimulation. .