Post-transcriptional control of anti-tumor immune responses

Abstract

Translation of mRNAs into proteins is a highly regulated step of gene expression. In cancer, post-transcriptional and translational control have a critical effect on transformation, controlling proliferation, survival, stemness or metastatic capacity of tumor cells. However, cancer development not only depends on cell-intrinsic properties, but it is also influenced by the tumor microenvironment (TME). mRNA translation is pivotal in this communication, as tumor cytokine production, vascularization promotion or immune recognition are translationally regulated processes. However, the role of translational control in other components of the TME is largely unknown.

Cytoplasmic polyadenylation element binding proteins (CPEBs) are a family of four (CPEB1-4) RNA binding proteins that regulate mRNA translation and stability. In the context of cancer, CPEB function, and in particular CPEB4, has been mostly studied in tumor cells, where it mainly acts as a tumor promoter. However, its role in different cell types of the TME is completely unexplored. In the present work, we characterized a novel role for CPEB4 in T cell mediated anti-tumor immunity. We observed that CPEB4 in T cells is required for an efficient anti-tumor effector response. CPEB4 is upregulated in activated and effector T cells by activation-induced endoplasmic reticulum (ER) stress and, in turn, it regulates mRNAs required for stress adaptation. Therefore, CPEB4- mediated gene expression control allows cellular adaptation to ER stress, improving T cell effector function and anti-tumor activity.