RT Journal Article
SR Electronic
T1 Internal checkpoint regulates T cell neoantigen reactivity and susceptibility to PD1 blockade
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2020.09.24.306571
DO 10.1101/2020.09.24.306571
A1 Douglas C. Palmer
A1 Beau R. Webber
A1 Yogin Patel
A1 Matthew J. Johnson
A1 Christine M. Kariya
A1 Walker S. Lahr
A1 Maria R. Parkhurst
A1 Jared J Gartner
A1 Todd D Prickett
A1 Frank J. Lowery
A1 Rigel J. Kishton
A1 Devikala Gurusamy
A1 Zulmarie Franco
A1 Suman K. Vodnala
A1 Miechaleen D. Diers
A1 Natalie K. Wolf
A1 Nicholas J. Slipek
A1 David H. McKenna
A1 Darin Sumstad
A1 Lydia Viney
A1 Tom Henley
A1 Tilmann Bürckstümmer
A1 Oliver Baker
A1 Ying Hu
A1 Chunhua Yan
A1 Daoud Meerzaman
A1 Kartik Padhan
A1 Winnie Lo
A1 Parisa Malekzadeh
A1 Li Jia
A1 Drew C. Deniger
A1 Shashank J. Patel
A1 Paul F. Robbins
A1 R. Scott McIvor
A1 Modassir Choudhry
A1 Steven A. Rosenberg
A1 Branden S. Moriarity
A1 Nicholas P. Restifo
YR 2020
UL http://biorxiv.org/content/early/2020/09/25/2020.09.24.306571.abstract
AB 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 PLCγ-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.Competing Interest StatementM.C. is a co-founder of Intima Bioscience. B.R.W, S.A.R, and B.S.M have received sponsored research support from Intima Bioscience. D.C.P., B.R. W, M.C., S.A.R., B.S.M, and N.P.R. have patents filed based on the findings described here.