PT  - JOURNAL ARTICLE
AU  - Elisa Arthofer
AU  - Krishnendu Chakraborty
AU  - Lydia Viney
AU  - Matthew J Johnson
AU  - Beau R. Webber
AU  - Branden S. Moriarity
AU  - Emil Lou
AU  - Modassir Choudhry
AU  - Christopher A. Klebanoff
AU  - Tom Henley
TI  - Genetic editing of <em>CISH</em> enhances T cell effector programs independently of immune checkpoint cell surface ligand expression
AID  - 10.1101/2021.08.17.456714
DP  - 2021 Jan 01
TA  - bioRxiv
PG  - 2021.08.17.456714
4099  - http://biorxiv.org/content/early/2021/08/17/2021.08.17.456714.short
4100  - http://biorxiv.org/content/early/2021/08/17/2021.08.17.456714.full
AB  - PD-1 acts as a negative regulator of T cell-mediated immune responses in the setting of persistent antigen expression, including cancer and chronic pathogen infections. Antibody-mediated blockade of the PD-1/PD-L1 axis benefits a subset of patients with highly immunogenic malignancies; however, many patients fail to respond due to a requirement for expression of the cell surface ligand PD-L1 within the tumor microenvironment. CISH is a member of a new class of intra-cellular immune checkpoint molecules that function downstream of the T cell receptor to regulate antigen-specific effector functions, including reactivity to cancer neoantigens. Herein, we employed multiplex CRISPR editing of primary human T cells to systematically compare the function of CISH deletion relative to PDCD1 (the gene encoding PD-1) and/or VSIG9 (the gene encoding TIGIT) in a model of neoantigen-mediated cancer cell cytolysis. PD-1 and TIGIT disruption enhanced cytolytic activity exclusively in the setting of high PD-L1 expression. In contrast, CISH inactivation enhanced antigen-specific cytolysis of tumor cells regardless of PD-L1 expression, including outperforming PD-1 and TIGIT disruption even in the presence of high PD-L1 tumor cells. Furthermore, we observed a synergistic increase in tumor cell killing when CISH and PD-1 or TIGIT are inactivated in combination, supporting the notion that these immune checkpoints regulate non-redundant pathways of T cell activation. Together, these data demonstrate that the intra-cellular immune checkpoint protein CISH can potentially enhance anti-tumor responses against a broad range of cancer types regardless of PD-L1 biomarker status.Competing Interest StatementThe authors have declared no competing interest.