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

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).

SUBMITTER: Skelly DA 

PROVIDER: S-EPMC12404271 | biostudies-literature | 2025 May

REPOSITORIES: biostudies-literature