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

Authors

Daniel A Skelly, The Jackson LaboratoryFollow
John P Graham, The Jackson LaboratoryFollow
Mingshan Cheng, The Jackson LaboratoryFollow
Mayuko Furuta, The Jackson LaboratoryFollow
Andrew Walter, The Jackson LaboratoryFollow
Thomas A Stoklasek, The Jackson LaboratoryFollow
Hongyuan Yang, The Jackson LaboratoryFollow
Timothy M Stearns, The Jackson LaboratoryFollow
Olivier Poirion, The Jackson LaboratoryFollow
Ji-Gang Zhang, The Jackson LaboratoryFollow
Jessica D S Grassmann, The Jackson LaboratoryFollow
Diane Luo, The Jackson LaboratoryFollow
William F Flynn, The Jackson LaboratoryFollow
Elise T Courtois, The Jackson LaboratoryFollow
Chih-Hao Chang, The Jackson LaboratoryFollow
David V. Serreze, The Jackson LaboratoryFollow
Francesca Menghi, The Jackson LaboratoryFollow
Laura G Reinholdt, The Jackson LaboratoryFollow
Edison Liu, The Jackson LaboratoryFollow

Document Type

Article

Publication Date

5-27-2025

Original Citation

Skelly D, Graham J, Cheng M, Furuta M, Walter A, Stoklasek T, Yang H, Stearns T, Poirion O, Zhang J, Grassmann J, Luo D, Flynn W, Courtois E, Chang C, Serreze DV, Menghi F, Reinholdt L, Liu E. Mapping the genetic landscape establishing a tumor immune microenvironment favorable for anti-PD-1 response. Cell Rep. 2025;44(5):115698.

Keywords

JMG, JGM, JCA, SS1, Animals, Tumor Microenvironment, Mice, Programmed Cell Death 1 Receptor, Immune Checkpoint Inhibitors, Quantitative Trait Loci, Mice, Inbred C57BL, Immunotherapy, Colorectal Neoplasms, Humans, Female, Cell Line, Tumor

JAX Source

Cell Rep. 2025;44(5):115698.

ISSN

2211-1247

PMID

40343794

DOI

https://doi.org/10.1016/j.celrep.2025.115698

Grant

This work was supported by an Aspire Award from The Mark Foundation for Cancer Research, United States (grant no. 19-036-ASP), the National Cancer Institute, United States (grant no. R01CA288836), the JAX Cancer Center’s Developmental Fund Award (P30 CA034196) and CATch Program, and the JAX Director’s Innovation Fund.

Abstract

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.

Creative Commons License

This work is licensed under a Creative Commons Attribution 4.0 International License.