Mapping the genetic landscape establishing a tumor immune microenvironment favorable for anti-PD-1 response

Mapping the genetic landscape establishing a tumor immune microenvironment favorable for anti-PD-1 response

Summary: Identifying host genetic factors modulating immune checkpoint inhibitor (ICI) efficacy is experimentally challenging. Our approach, utilizing the Collaborative Cross mouse genetic resource, fixes the tumor genomic configuration while varying host genetics. We find that response to anti-PD-1...

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Main Authors: Daniel A. Skelly, John P. Graham, Mingshan Cheng, Mayuko Furuta, Andrew Walter, Thomas A. Stoklasek, Hongyuan Yang, Timothy M. Stearns, Olivier Poirion, Ji-Gang Zhang, Jessica D.S. Grassmann, Diane Luo, William F. Flynn, Elise T. Courtois, Chih-Hao Chang, David V. Serreze, Francesca Menghi, Laura G. Reinholdt, Edison T. Liu
Format: Article
Language:English
Published: Elsevier 2025-05-01
Series:Cell Reports
Subjects:
CP: Cancer
CP: Immunology
Online Access:http://www.sciencedirect.com/science/article/pii/S2211124725004693
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Summary:Summary: Identifying host genetic factors modulating immune checkpoint inhibitor (ICI) efficacy is experimentally challenging. Our approach, utilizing the Collaborative Cross mouse genetic resource, fixes the tumor genomic configuration while varying host genetics. We find that response to anti-PD-1 (aPD1) immunotherapy is significantly heritable in four distinct murine tumor models (H2: 0.18–0.40). For the MC38 colorectal carcinoma system, we map four significant ICI response quantitative trait loci (QTLs) with significant epistatic interactions. The differentially expressed genes within these QTLs that define responder genetics are highly enriched for processes involving antigen processing and presentation, allograft rejection, and graft vs. host disease (all p < 1 × 10−10). Functional blockade of two top candidate immune targets, GM-CSF and IL-2RB, completely abrogates the MC38 transcriptional response to aPD1 therapy. Thus, our in vivo experimental platform is a powerful approach for discovery of host genetic factors that establish the tumor immune microenvironment propitious for ICI response.
ISSN:2211-1247

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