Overcoming Tumor-Intrinsic Therapeutic Resistance to Immunotherapies

University Of Alabama At Birmingham, Birmingham AL

Investigators

Linked publications & trials

Abstract

PROJECT SUMMARY/ABSTRACT Immune checkpoint blockers (ICBs) such as anti-CTLA-4 and anti-PD-1 are revolutionizing the field of cancer care, emerging as the fourth pillar of cancer therapies. To date, more than 60 approvals of utilizing ICBs to treat various types of cancer have been granted by the FDA. Despite their transformative response, the overall efficacy of ICBs is limited to a small subset of cancer patients, because of therapeutic resistance. We and others recently found that loss of IFN- signaling genes in advanced melanoma and colon cancer is a major mechanism of resistance to ICBs. Therefore, identifying therapeutic strategies capable of overcoming this resistance is of utmost importance. Based on our preliminary data, we hypothesize that deletion of IFN- signaling in tumor cells (IFNR1KO) augments the Myc-glutaminolysis pathway and metabolically forges an “immune-cold” tumor microenvironment, conferring therapeutic resistance to ICBs. In Aim 1, we will determine metabolic mechanisms by which the IFNR1-Myc axis regulates therapeutic response to ICBs in both mouse and human melanoma. In Aim 2, we will dissect cellular mechanisms by which the IFNR1-Myc axis mediates ICB resistance, and attempt to target Myc-driven metabolic pathways to overcome ICB resistance. We will also test these metabolic modulators as potential effective strategies to sensitize “immune cold” IFNR1KO tumors to ICBs. While metabolic reprogramming in tumor cells has been correlated with therapeutic resistance to chemotherapies, to the best of our knowledge, there is no prior study directly linking metabolic reprogramming to therapeutic resistance to ICBs. As such, we predict insights gained from our studies will significantly advance our understanding of how metabolic reprograming associated with tumor-intrinsic alterations coordinates therapeutic responses of ICBs. These studies may manifest “targeted” therapies for cancer patients who are resistant to ICBs.