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

Setsuko Mise-Omata; Makoto Ando; Tanakorn Srirat; Kensuke Nakagawara; Taeko Hayakawa; Mana Iizuka-Koga; Hiroshi Nishimasu; Osamu Nureki; Minako Ito; Akihiko Yoshimura

doi:10.1016/j.celrep.2023.112940

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

Cell Rep. 2023 Aug 29;42(8):112940. doi: 10.1016/j.celrep.2023.112940. Epub 2023 Aug 14.

Authors

Affiliations

¹ Department of Microbiology and Immunology, Keio University School of Medicine, Tokyo, Japan. Electronic address: setsukomise@gmail.com.
² Department of Microbiology and Immunology, Keio University School of Medicine, Tokyo, Japan.
³ Structural Biology Division, Research Center for Advanced Science and Technology, The University of Tokyo, Tokyo, Japan.
⁴ Department of Biological Science, Graduate School of Science, The University of Tokyo, Tokyo, Japan.
⁵ Division of Allergy and Immunology, Medical Institute of Bioregulation, Kyushu University, Fukuoka, Japan.
⁶ Department of Microbiology and Immunology, Keio University School of Medicine, Tokyo, Japan. Electronic address: yoshimura@keio.jp.

PMID: 37582370
DOI: 10.1016/j.celrep.2023.112940

Abstract

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.

Keywords: CAR-T therapy; CP: Cancer; IL-6; anti-tumor immunity; cytotoxic T cell; effector T cells; mitochondrial fitness; regulatory T cells; suppressor of cytokine signaling 3.