Suppressors of cytokine signaling: Potential immune checkpoint molecules for cancer immunotherapy

Inhibition of immune checkpoint molecules, PD‐1 and CTLA4, has been shown to be a promising cancer treatment. PD‐1 and CTLA4 inhibit TCR and co‐stimulatory signals. The third T cell activation signal represents the signals from the cytokine receptors. The cytokine interferon‐γ (IFNγ) plays an important role in anti‐tumor immunity by activating cytotoxic T cells (CTLs). Most cytokines use the Janus kinase (JAK)/signal transducer and activator of transcription (STAT) pathway, and the suppressors of cytokine signaling (SOCS) family of proteins are major negative regulators of the JAK/STAT pathway. Among SOCS proteins, CIS, SOCS1, and SOCS3 proteins can be considered the third immunocheckpoint molecules since they regulate cytokine signals that control the polarization of CD4+ T cells and the maturation of CD8+ T cells. This review summarizes recent progress on CIS, SOCS1, and SOCS3 in terms of their anti‐tumor immunity and potential applications. Inhibition of immune‐checkpoint molecules, PD‐1 and CTLA4, has been shown to be a promising cancer treatment. SOCS proteins are the third immune‐checkpoint molecules that inhibit cytokine signaling. This review is focusing on the mechanism of inhibition of cytokine signaling by CIS, SOCS1 and SOCS3, and their relationship to T cell biology and anti‐tumor immunity.