The isolated immune cell according to claim 121, wherein the endogenous PROCR, PRDM1 and c-MAF, or PDPN gene has been modified, whereby the cell comprises downregulated or abolished expression or activity of PROCR, PRDM1 and c-MAF, or PDPN.ġ24. The isolated immune cell according to claim 121, wherein the immune cell is a CD8+ T cell that displays tumor specificity.ġ23. An isolated immune cell modified to comprise an altered expression or activity of, or modified to comprise an agent capable of inducibly altering expression or activity of, one or more of protein C receptor (PROCR), PRDM1 and c-MAF, and Podoplanin (PDPN).ġ22. This critical molecular circuit underlies the co-expression of co-inhibitory receptors in dysfunctional T cells and identifies novel regulators of T cell dysfunction.ġ21. The present invention further provides the novel discovery that the transcription factors Prdm1 and c-Maf cooperatively regulate the expression of the co-inhibitory receptor module. The present invention provides a novel immunoregulatory network as well as novel cell surface molecules that have an inhibitory function in the tumor microenvironment. The immunoregulatory cytokine IL-27 induces a gene module in T cells that includes several known co-inhibitory receptors (Tim-3, Lag-3, and TIGIT). While co-inhibitory receptors are co-expressed, the triggers that induce them and the transcriptional regulators that drive their co-expression have not been identified.
Therapeutic blockade of these receptors has clinical efficacy in the treatment of cancer. Dysfunctional or exhausted T cells arise in chronic diseases including chronic viral infections and cancer, and express high levels of co-inhibitory receptors.
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