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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| Language: | English |
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Elsevier
2025-05-01
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| Series: | Cell Reports |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2211124725004693 |
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| author | 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 |
| author_facet | 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 |
| author_sort | Daniel A. Skelly |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-d53d8f6672db4f648dba14e31189ee06 |
| institution | OA Journals |
| issn | 2211-1247 |
| language | English |
| publishDate | 2025-05-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Cell Reports |
| spelling | doaj-art-d53d8f6672db4f648dba14e31189ee062025-08-20T02:15:20ZengElsevierCell Reports2211-12472025-05-0144511569810.1016/j.celrep.2025.115698Mapping the genetic landscape establishing a tumor immune microenvironment favorable for anti-PD-1 responseDaniel A. Skelly0John P. Graham1Mingshan Cheng2Mayuko Furuta3Andrew Walter4Thomas A. Stoklasek5Hongyuan Yang6Timothy M. Stearns7Olivier Poirion8Ji-Gang Zhang9Jessica D.S. Grassmann10Diane Luo11William F. Flynn12Elise T. Courtois13Chih-Hao Chang14David V. Serreze15Francesca Menghi16Laura G. Reinholdt17Edison T. Liu18The Jackson Laboratory for Mammalian Genetics, Bar Harbor, ME 04609, USAThe Jackson Laboratory for Mammalian Genetics, Bar Harbor, ME 04609, USAThe Jackson Laboratory, Sacramento, CA 95838, USAThe Jackson Laboratory for Genomic Medicine, Farmington, CT 06032, USAThe Jackson Laboratory for Mammalian Genetics, Bar Harbor, ME 04609, USAThe Jackson Laboratory for Genomic Medicine, Farmington, CT 06032, USAThe Jackson Laboratory, Sacramento, CA 95838, USAThe Jackson Laboratory for Mammalian Genetics, Bar Harbor, ME 04609, USAThe Jackson Laboratory for Genomic Medicine, Farmington, CT 06032, USAThe Jackson Laboratory for Mammalian Genetics, Bar Harbor, ME 04609, USASingle Cell Biology Lab, The Jackson Laboratory for Genomic Medicine, Farmington, CT 06032, USASingle Cell Biology Lab, The Jackson Laboratory for Genomic Medicine, Farmington, CT 06032, USASingle Cell Biology Lab, The Jackson Laboratory for Genomic Medicine, Farmington, CT 06032, USASingle Cell Biology Lab, The Jackson Laboratory for Genomic Medicine, Farmington, CT 06032, USA; OB/Gyn Department, UConn Health, Farmington, CT 06032, USAThe Jackson Laboratory for Mammalian Genetics, Bar Harbor, ME 04609, USAThe Jackson Laboratory for Mammalian Genetics, Bar Harbor, ME 04609, USAThe Jackson Laboratory for Genomic Medicine, Farmington, CT 06032, USAThe Jackson Laboratory for Mammalian Genetics, Bar Harbor, ME 04609, USAThe Jackson Laboratory for Genomic Medicine, Farmington, CT 06032, USA; Corresponding authorSummary: 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.http://www.sciencedirect.com/science/article/pii/S2211124725004693CP: CancerCP: Immunology |
| spellingShingle | 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 Mapping the genetic landscape establishing a tumor immune microenvironment favorable for anti-PD-1 response Cell Reports CP: Cancer CP: Immunology |
| title | Mapping the genetic landscape establishing a tumor immune microenvironment favorable for anti-PD-1 response |
| title_full | Mapping the genetic landscape establishing a tumor immune microenvironment favorable for anti-PD-1 response |
| title_fullStr | Mapping the genetic landscape establishing a tumor immune microenvironment favorable for anti-PD-1 response |
| title_full_unstemmed | Mapping the genetic landscape establishing a tumor immune microenvironment favorable for anti-PD-1 response |
| title_short | Mapping the genetic landscape establishing a tumor immune microenvironment favorable for anti-PD-1 response |
| title_sort | mapping the genetic landscape establishing a tumor immune microenvironment favorable for anti pd 1 response |
| topic | CP: Cancer CP: Immunology |
| url | http://www.sciencedirect.com/science/article/pii/S2211124725004693 |
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