Genome-Wide CRISPR Screens Using Isogenic Cells Reveal Vulnerabilities Conferred by Loss of Tumor Suppressors

Authors

Rodney Cheng-En Hsieh
Sunil Krishnan
Ren-Chin Wu
Akash R Boda
Arthur Liu
Michelle Winkler
Wen-Hao Hsu
Steven Hsesheng Lin
Mien-Chie Hung
Li-Chuan Chan
Krithikaa Rajkumar Bhanu
Anupallavi Srinivasamani
Ricardo Alexandre De Azevedo
Yung-Chih Chou
Ronald A DePinho
Matthew Gubin
Eduardo Vilar
Chao Hsien Chen
Ravaen Slay
Priyamvada Jayaprakash
Shweta Mahendra Hegde
Genevieve Hartley
Spencer T Lea
Rishika Prasad
Brittany Morrow
Coline Agnes Couillault
Madeline Steiner
Chun-Chieh Wang
Bhanu Prasad Venkatesulu
Cullen Taniguchi
Yon Son Betty Kim
Junjie Chen
Nils-Petter Rudqvist
Michael A Curran

Publication Date

6-10-2022

Journal

Science Immunology

Abstract

Radiotherapy (RT) of colorectal cancer (CRC) can prime adaptive immunity against tumor-associated antigen (TAA)-expressing CRC cells systemically. However, abscopal tumor remissions are extremely rare, and the postirradiation immune escape mechanisms in CRC remain elusive. Here, we found that irradiated CRC cells used ATR-mediated DNA repair signaling pathway to up-regulate both CD47 and PD-L1, which through engagement of SIRPα and PD-1, respectively, prevented phagocytosis by antigen-presenting cells and thereby limited TAA cross-presentation and innate immune activation. This postirradiation CD47 and PD-L1 up-regulation was observed across various human solid tumor cells. Concordantly, rectal cancer patients with poor responses to neoadjuvant RT exhibited significantly elevated postirradiation CD47 levels. The combination of RT, anti-SIRPα, and anti-PD-1 reversed adaptive immune resistance and drove efficient TAA cross-presentation, resulting in robust TAA-specific CD8 T cell priming, functional activation of T effectors, and increased T cell clonality and clonal diversity. We observed significantly higher complete response rates to RT/anti-SIRPα/anti-PD-1 in both irradiated and abscopal tumors and prolonged survival in three distinct murine CRC models, including a cecal orthotopic model. The efficacy of triple combination therapy was STING dependent as knockout animals lost most benefit of adding anti-SIRPα and anti-PD-1 to RT. Despite activation across the myeloid stroma, the enhanced dendritic cell function accounts for most improvements in CD8 T cell priming. These data suggest ATR-mediated CD47 and PD-L1 up-regulation as a key mechanism restraining radiation-induced immune priming. RT combined with SIRPα and PD-1 blockade promotes robust antitumor immune priming, leading to systemic tumor regressions.

Keywords

Animals, Antigens, Neoplasm, Ataxia Telangiectasia Mutated Proteins, B7-H1 Antigen, CD47 Antigen, Colorectal Neoplasms, Humans, Mice, Programmed Cell Death 1 Receptor, Up-Regulation

DOI

10.1126/sciimmunol.abl9330

PMID

35687697

PMCID

PMC9373855

PubMedCentral® Posted Date

8-12-2022

PubMedCentral® Full Text Version

Author MSS

Published Open-Access

yes