Article
作者: Meerzaman, Daoud ; Deniger, Drew C ; Slipek, Nicholas J ; Patel, Shashank J ; Hu, Ying ; Choudhry, Modassir ; Yan, Chunhua ; Jia, Li ; Prickett, Todd D ; Webber, Beau R ; Kariya, Christine M ; Gartner, Jared J ; Henley, Tom ; Wolf, Natalie K ; Lahr, Walker S ; McIvor, R Scott ; Lowery, Frank J ; Moriarity, Branden S ; Baker, Oliver ; Lo, Winnie ; Patel, Yogin ; Diers, Miechaleen D ; Viney, Lydia ; Robbins, Paul F ; Bürckstümmer, Tilmann ; Franco, Zulmarie ; Gurusamy, Devikala ; Malekzadeh, Parisa ; Johnson, Matthew J ; Rosenberg, Steven A ; Restifo, Nicholas P ; Palmer, Douglas C ; Vodnala, Suman K ; Kishton, Rigel J ; Parkhurst, Maria R ; Sumstad, Darin ; Padhan, Kartik ; McKenna, David H
BACKGROUND:Adoptive transfer of tumor-infiltrating lymphocytes (TIL) fails to consistently elicit tumor rejection. Manipulation of intrinsic factors that inhibit T cell effector function and neoantigen recognition may therefore improve TIL therapy outcomes. We previously identified the cytokine-induced SH2 protein (CISH) as a key regulator of T cell functional avidity in mice. Here, we investigate the mechanistic role of CISH in regulating human T cell effector function in solid tumors and demonstrate that CRISPR/Cas9 disruption of CISH enhances TIL neoantigen recognition and response to checkpoint blockade.
METHODS:Single-cell gene expression profiling was used to identify a negative correlation between high CISH expression and TIL activation in patient-derived TIL. A GMP-compliant CRISPR/Cas9 gene editing process was developed to assess the impact of CISH disruption on the molecular and functional phenotype of human peripheral blood T cells and TIL. Tumor-specific T cells with disrupted Cish function were adoptively transferred into tumor-bearing mice and evaluated for efficacy with or without checkpoint blockade.
FINDINGS:CISH expression was associated with T cell dysfunction. CISH deletion using CRISPR/Cas9 resulted in hyper-activation and improved functional avidity against tumor-derived neoantigens without perturbing T cell maturation. Cish knockout resulted in increased susceptibility to checkpoint blockade in vivo.
CONCLUSIONS:CISH negatively regulates human T cell effector function, and its genetic disruption offers a novel avenue to improve the therapeutic efficacy of adoptive TIL therapy.
FUNDING:This study was funded by Intima Bioscience, U.S. and in part through the Intramural program CCR at the National Cancer Institute.