Palmer and Webber et al. demonstrated that cytokine-induced SH2 protein (CISH) negatively regulated human T cell function and reactivity to neoantigens, and its genetic disruption improved the efficacy of adoptive TIL therapy. CISH KO in neoantigen-selected TILs enhanced cytokine polyfunctionality, cytolysis, and reactivity against identified neoantigens, and restored TIL reactivity against universal hot spot p53 mutations. CISH KO enhanced T cell proliferation, activation, and metabolism, but not maturation. The combination of CISH deletion in TILs and PD-1 blockade resulted in tumor regression and long-term survival in B16 melanoma-bearing mice.
Contributed by Shishir Pant
ABSTRACT: While neoantigen-specific tumor infiltrating lymphocytes (TIL) can be derived from in antigen- expressing tumors, their adoptive transfer fails to consistently elicit durable tumor regression. There has been much focus on the role of activation/exhaustion markers such as PD1, CD39 and TOX in TIL senescence. We found these markers were inversely expressed to Cytokine-Induced SH2 protein (CISH), a negative regulator of TCR signaling and tumor immunity in mice. To evaluate the physiological role of CISH in human TIL we developed a high-efficiency CRIPSR-based method to knock out CISH in fully mature TIL. CISH KO resulted in increased T cell receptor (TCR) avidity, tumor cytolysis and neoantigen recognition. CISH expression in the tumor resections correlated with TIL inactivity against p53 hotspot mutations and CISH KO in TIL unmasked reactivity against these universal neoantigens. While CISH KO resulted in T cell hyperactivation and expansion it did not alter maturation, perhaps by preferential PLC -1 and not AKT inhibition. Lastly, CISH KO in T cells increased PD1 expression and the adoptive transfer of Cish KO T cells synergistically combines with PD1 antibody blockade resulting in durable tumor regression and survival in a preclinical animal model. These data offer new insights into the regulation of neoantigen recognition, expression of activation/exhaustion markers, and functional/maturation signals in tumor-specific T cells.
Author Info: (1) Surgery Branch,National Cancer Institute (NCI),National Institutes of Health,Bethesda,Maryland,USA. (2) Department of Pediatrics, University of Minnesota,Minneapolis,MN,USA. (3
Author Info: (1) Surgery Branch,National Cancer Institute (NCI),National Institutes of Health,Bethesda,Maryland,USA. (2) Department of Pediatrics, University of Minnesota,Minneapolis,MN,USA. (3) Masonic Cancer Center ,University of Minnesota, Minneapolis,MN,USA. (4) Center for Genome Engineering,University of Minnesota,Minneapolis,MN,USA. (5) Department of Laboratory Medicine and Pathology,University of Minnesota,Minneapolis,Minnesota,USA. (6) Molecular and Cellular Therapeutics,University of Minnesota,SaintPaul,Minnesota,USA. (7) Intima Bioscience,Inc. NewYork,NY,USA. (8) The Center for Biomedical Informatics and Information Technology (CBIIT), National Institutes of Health, Bethesda, Maryland, USA, (9) National Institute of Allergy and Infectious Disease (NIAID), National Institutes of Health, Bethesda, Maryland, USA. (10)Department of Genetics, Cell Biology and Development, University of Minnesota, MN, USA. *These authors contributed equally.
