Cancer genes disfavoring T cell immunity identified via integrated systems approach

Rigel J Kishton; Shashank J Patel; Amy E Decker; Suman K Vodnala; Maggie Cam; Tori N Yamamoto; Yogin Patel; Madhusudhanan Sukumar; Zhiya Yu; Michelle Ji; Amanda N Henning; Devikala Gurusamy; Douglas C Palmer; Roxana A Stefanescu; Andrew T Girvin; Winifred Lo; Anna Pasetto; Parisa Malekzadeh; Drew C Deniger; Kris C Wood; Neville E Sanjana; Nicholas P Restifo

doi:10.1016/j.celrep.2022.111153

Cancer genes disfavoring T cell immunity identified via integrated systems approach

Cell Rep. 2022 Aug 2;40(5):111153. doi: 10.1016/j.celrep.2022.111153.

Authors

Rigel J Kishton¹, Shashank J Patel², Amy E Decker³, Suman K Vodnala², Maggie Cam⁴, Tori N Yamamoto⁵, Yogin Patel², Madhusudhanan Sukumar², Zhiya Yu², Michelle Ji², Amanda N Henning², Devikala Gurusamy², Douglas C Palmer², Roxana A Stefanescu⁶, Andrew T Girvin⁶, Winifred Lo⁷, Anna Pasetto⁷, Parisa Malekzadeh⁷, Drew C Deniger⁷, Kris C Wood³, Neville E Sanjana⁸, Nicholas P Restifo⁹

Affiliations

¹ Surgery Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892, USA; Center for Cell-Based Therapy, National Cancer Institute, Bethesda, MD 20892, USA. Electronic address: [email protected].
² Surgery Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892, USA; Center for Cell-Based Therapy, National Cancer Institute, Bethesda, MD 20892, USA.
³ Department of Pharmacology and Cancer Biology, Duke University School of Medicine, Durham, NC 27710, USA.
⁴ CCR Collaborative Bioinformatics Resource (CCBR), Office of Science and Technology Resources, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892, USA.
⁵ Surgery Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892, USA; Center for Cell-Based Therapy, National Cancer Institute, Bethesda, MD 20892, USA; Immunology Graduate Group, University of Pennsylvania, Philadelphia, PA 19104, USA.
⁶ Palantir Technologies, Washington, DC 20007, USA.
⁷ Surgery Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892, USA.
⁸ New York Genome Center, New York, NY 10013, USA; Department of Biology, New York University, New York, NY 10003, USA.
⁹ Surgery Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892, USA; Center for Cell-Based Therapy, National Cancer Institute, Bethesda, MD 20892, USA. Electronic address: [email protected].

Abstract

Adoptive T cell therapies (ACT) have been curative for a limited number of cancer patients. The sensitization of cancer cells to T cell killing may expand the benefit of these therapies for more patients. To this end, we use a three-step approach to identify cancer genes that disfavor T cell immunity. First, we profile gene transcripts upregulated by cancer under selection pressure from T cell killing. Second, we identify potential tumor gene targets and pathways that disfavor T cell killing using signaling pathway activation libraries and genome-wide loss-of-function CRISPR-Cas9 screens. Finally, we implement pharmacological perturbation screens to validate these targets and identify BIRC2, ITGAV, DNPEP, BCL2, and ERRα as potential ACT-drug combination candidates. Here, we establish that BIRC2 limits antigen presentation and T cell recognition of tumor cells by suppressing IRF1 activity and provide evidence that BIRC2 inhibition in combination with ACT is an effective strategy to increase efficacy.

Keywords: CP: Cancer; CP: Immunology; CRISPR screen; cell therapy; combination immunotherapy; gain-of-function screen; immunotherapy resistance.

Published by Elsevier Inc.

Publication types

Research Support, Non-U.S. Gov't
Research Support, N.I.H., Intramural
Research Support, N.I.H., Extramural

MeSH terms

Antigen Presentation
CRISPR-Cas Systems / genetics
Humans
Neoplasms* / genetics
Oncogenes
Systems Analysis
T-Lymphocytes*

Abstract

Publication types

MeSH terms

Grants and funding