Over the past decade, immune checkpoint blockers (ICBs) such as anti-CTLA-4 and anti-PD-1 have rapidly emerged as a major pillar of cancer care. However, despite their unprecedented clinical successes, overall efficacy of ICBs is limited, due to the rather common therapeutic resistance in most patients. As original efforts to understand why, Dr. Shi and others revealed that loss of IFN-\u0263 signaling genes in tumor cells is a major mechanism of resistance to ICBs, but the underlying mechanism has since then remained unknown. Consequently, it has been largely unexplored how to overcome this resistance. Intriguingly, Dr. Shi\u2019s preliminary studies using tumor models lacking functional IFN-\u0263 signaling identified constitutively active Janus Kinase 1\/2 (JAK1\/2), as a result of aberrant\u00a0metabolic reprogramming. Together, they forge an \u201cimmune-cold\u201d tumor microenvironment and drive ICB resistance. <\/p>\n\n\n\n
In Aim 1, Dr. Shi will decipher the metabolic mechanism(s) underlying ICB resistance. In Aim 2, he will determine the molecular and cellular mechanisms by which loss of IFN-\u0263 signaling in tumor cells promotes ICB resistance and will utilize clinically-approved and -tested inhibitors to overcome this ICB resistance. While metabolic reprogramming in tumor cells has been associated with therapeutic resistance to chemotherapy and adoptive immunotherapy, to the best of our knowledge, it remains to be established whether metabolic reprograming is the driving force or a mere consequence of ICB resistance. Insights gained from Dr. Shi\u2019s studies will shed light on this for the first time and advance mechanistic understanding of how tumor-intrinsic changes affect anti-tumor function of T cells. These studies may manifest \u201ctargeted\u201d therapies to overcome ICB resistance and guide future design of clinical trials, which will greatly expand the patient population that can benefit from these novel ICBs, a pressing medical need.<\/p>\n\n\n\n
University of Alabama at Birmingham | All Cancers | 2022<\/p>\n\n\n\n