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

• Published in: Cell reports (Cambridge) Vol. 42; no. 8; p. 112940
• Main Authors: Mise-Omata, Setsuko, Ando, Makoto, Srirat, Tanakorn, Nakagawara, Kensuke, Hayakawa, Taeko, Iizuka-Koga, Mana, Nishimasu, Hiroshi, Nureki, Osamu, Ito, Minako, Yoshimura, Akihiko
• Format: Journal Article
• Language: English
• Published: Elsevier Inc 29.08.2023; Elsevier
• Subjects: anti-tumor immunity; CAR-T therapy; CP: Cancer; cytotoxic T cell; effector T cells; IL-6; mitochondrial fitness; regulatory T cells; suppressor of cytokine signaling 3; regulatory T cells; suppressor of cytokine signaling 3; mitochondrial fitness; effector T cells; CP: Cancer; anti-tumor immunity; cytotoxic T cell; CAR-T therapy; IL-6
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2023.112940

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. [Display omitted] •Deletion of SOCS3 in T cells improves anti-tumor responses•IL-6 is the cytokine responsible for enhancing the response in Socs3−/− T cells•SOCS3 deficiency in T cells promotes glycolysis and effector functions•SOCS3 knockdown in human CAR-T cells enhances anti-tumor responses Mise-Omata et al. demonstrate that the deletion of SOCS3 in T cells enhances the anti-tumor response by promoting the differentiation of exhausted progenitor T cells into effector cells. This effect is driven by alteration of the IL-6 signaling, which leads to enhanced glycolysis and improved mitochondrial fitness.