CD4 helper programs that regulate intratumoral immunity

Icahn School Of Medicine At Mount Sinai, New York NY

Investigators

Abstract

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. .