Lewis Zhichang Shi, PhD, CLIP Investigator University of Alabama at Birmingham 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-ɣ 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’s preliminary studies using tumor models lacking functional IFN-ɣ signaling identified constitutively active Janus Kinase 1/2 (JAK1/2), as a result of aberrant metabolic reprogramming. Together, they forge an “immune-cold” tumor microenvironment and drive ICB resistance. 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-ɣ 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’s 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 “targeted” 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. Projects and Grants Discovering and targeting tumor-intrinsic metabolic checkpoints to overcome immunotherapy resistance University of Alabama at Birmingham | All Cancers | 2022 Publications Shen, H., Huang, F., Zhang, X. et al. Selective suppression of melanoma lacking IFN-γ pathway by JAK inhibition depends on T cells and host TNF signaling. Nat Commun 13, 5013 (2022)
