SOCS3 deletion in effector T cells confers an anti-tumorigenic role of IL-6 to the pro-tumorigenic cytokine [scRNA-seq]

Interleukin (IL)-6 is abundantly expressed in the tumor microenvironment and is associated with poor patient outcomes. Here, we demonstrate that the deletion of the suppressor of cytokine signaling 3 (SOCS3) in T cells potentiates anti-tumor immune responses by conferring the anti-tumorigenic function of IL-6 in mouse and human models. In Socs3-deficient CD8+ T cells, IL-6 upregulates the expression of type I interferon (IFN)-regulated genes and enhances the anti-tumor effector function of T cells, while also modifying mitochondrial fitness to increase mitochondrial membrane potential and reactive oxygen species (ROS) levels and to promote metabolic glycolysis in the energy state. Furthermore, Socs3 deficiency reduces regulatory T cells and increases T helper 1 (Th1) cells. SOCS3 knockdown in human chimeric antigen receptor T (CAR-T) cells exhibits a strong anti-tumor response in humanized mice. Thus, genetic disruption of SOCS3 offers an avenue to improve the therapeutic efficacy of adoptive T cell therapy. Overall design: MC38 cells, murine colon adenocarcinoma cells, were subcutaneously injected in the flanks of WT Socs3f/f or Cd4Cre Socs3f/f mice. CD3e+ TCRb+ T cells were isolated from tumor mass 12 days after tumor inoculation for scRNAseq analysis.