LAUSR

In a recent article, the authors and colleagues identified a new gene module that is induced by the regulatory cytokine, interleukin-27 (IL-27), and is found in multiple non-responsive T-cell states, such as exhaustion, dysfunction and tolerance. This study uncovered novel immune checkpoint molecules poised to become therapeutic targets. Furthermore, PRDM1 and c-MAF were identified as key transcription factors driving this gene module with the potential to control tumor immunity and autoimmunity. Multiple co-stimulatory and co-inhibitory molecules, as well as cytokines, play an important role in determining T-cell phenotype in chronic disease. In chronic autoimmune-mediated disease, such as multiple sclerosis, immune cells – especially T cells – are involved in the pathophysiology of long-term disease course. Although many co-inhibitory molecules that modulate T-cell phenotype in autoimmune diseases have been investigated, it was unclear whether there is a common anchor underlying the expression of these molecules. Here, using single-cell RNA-seq and single-cell mass cytometry, the author and colleagues showed the co-expression of these co-inhibitory molecules in the highly immunosuppressive tumor microenvironment. The core of the expression consisted of known co-inhibitory molecules, such as PD-1, TIM-3, LAG-3 and TIGIT, and coexpressed with multiple new cell-surface receptors. To identify the common regulator of these co-inhibitory molecules, the authors focused on the immunoregulatory cytokine, IL-27, as it has been shown to induce IL-10-secreting Tr1 cells that are immune suppressive and ameliorate experimental autoimmune encephalomyelitis, a murine experimental model of multiple sclerosis. In line with this, accumulating data show that IL-27 induces co-inhibitory molecules, such as PD-L1 or TIM-3. The authors showed that IL-27 induces the core co-inhibitory molecules, which are part of a larger co-inhibitory gene module that is also found in exhausted T cells in chronic viral infection, antigen-specific and non-specific immune tolerance, as well as dysfunctional T cells in the tumor microenvironment. The authors chose two cell-surface receptors that are part of the co-inhibitory gene module, activated protein C receptor and podoplanin, for functional validation in a tumor model. Furthermore, computational network analysis of the co-inhibitory gene module identified that the transcription factors, PRDM1 and c-MAF, cooperate to regulate these co-inhibitory receptors. Indeed, these two transcription factors were the key to controlling expression of the entire co-inhibitory gene module, as well as the immune response to tumors (Fig. 1). These findings deepen our understanding of the molecular circuitry underlying T-cell co-inhibitory receptor expression. As well as discovering a new target for tumor immunotherapy, the authors identified the transcription factors that are key to controlling co-inhibitory receptor expression. This knowledge contributes greatly to the understanding