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Mapping the genetic landscape establishing a tumor immune microenvironment favorable for anti-PD-1 response in mice and humans.
Skelly, Daniel A; Graham, John P; Cheng, Mingshan; Furuta, Mayuko; Walter, Andrew; Stoklasek, Thomas A; Yang, Hongyuan; Stearns, Timothy M; Poirion, Olivier; Zhang, Ji-Gang; Grassmann, Jessica D S; Luo, Diane; Flynn, William F; Courtois, Elise T; Chang, Chih-Hao; Serreze, David V; Menghi, Francesca; Reinholdt, Laura G; Liu, Edison T.
Afiliación
  • Skelly DA; The Jackson Laboratory for Mammalian Genetics, Bar Harbor, ME, USA.
  • Graham JP; The Jackson Laboratory for Mammalian Genetics, Bar Harbor, ME, USA.
  • Cheng M; The Jackson Laboratory, Sacramento, CA, USA.
  • Furuta M; The Jackson Laboratory for Genomic Medicine, Farmington, CT, USA.
  • Walter A; The Jackson Laboratory for Mammalian Genetics, Bar Harbor, ME, USA.
  • Stoklasek TA; The Jackson Laboratory for Genomic Medicine, Farmington, CT, USA.
  • Yang H; The Jackson Laboratory, Sacramento, CA, USA.
  • Stearns TM; The Jackson Laboratory for Mammalian Genetics, Bar Harbor, ME, USA.
  • Poirion O; The Jackson Laboratory for Genomic Medicine, Farmington, CT, USA.
  • Zhang JG; The Jackson Laboratory for Mammalian Genetics, Bar Harbor, ME, USA.
  • Grassmann JDS; Single Cell Biology Lab, The Jackson Laboratory for Genomic Medicine, Farmington, CT, USA.
  • Luo D; Single Cell Biology Lab, The Jackson Laboratory for Genomic Medicine, Farmington, CT, USA.
  • Flynn WF; Single Cell Biology Lab, The Jackson Laboratory for Genomic Medicine, Farmington, CT, USA.
  • Courtois ET; Single Cell Biology Lab, The Jackson Laboratory for Genomic Medicine, Farmington, CT, USA.
  • Chang CH; OB/Gyn Department, UConn Health, Farmington, CT, USA.
  • Serreze DV; The Jackson Laboratory for Mammalian Genetics, Bar Harbor, ME, USA.
  • Menghi F; The Jackson Laboratory for Mammalian Genetics, Bar Harbor, ME, USA.
  • Reinholdt LG; The Jackson Laboratory for Genomic Medicine, Farmington, CT, USA.
  • Liu ET; The Jackson Laboratory for Mammalian Genetics, Bar Harbor, ME, USA.
bioRxiv ; 2024 Jul 16.
Article en En | MEDLINE | ID: mdl-39071392
ABSTRACT
Identifying host genetic factors modulating immune checkpoint inhibitor (ICI) efficacy has been experimentally challenging because of variations in both host and tumor genomes, differences in the microbiome, and patient life exposures. Utilizing the Collaborative Cross (CC) multi-parent mouse genetic resource population, we developed an approach that fixes the tumor genomic configuration while varying host genetics. With this approach, we discovered that response to anti-PD-1 (aPD1) immunotherapy was significantly heritable in four distinct murine tumor models (H2 between 0.18-0.40). For the MC38 colorectal carcinoma system (H2 = 0.40), we mapped four significant ICI response quantitative trait loci (QTL) localized to mouse chromosomes (mChr) 5, 9, 15 and 17, and identified significant epistatic interactions between specific QTL pairs. Differentially expressed genes within these QTL were highly enriched for immune genes and pathways mediating allograft rejection and graft vs host disease. Using a cross species analytical approach, we found a core network of 48 genes within the four QTLs that showed significant prognostic value for overall survival in aPD1 treated human cohorts that outperformed all other existing validated immunotherapy biomarkers, especially in human tumors of the previously defined immune subtype 4. Functional blockade of two top candidate immune targets within the 48 gene network, GM-CSF and high affinity IL-2/IL-15 signaling, completely abrogated the MC38 tumor transcriptional response to aPD1 therapy in vivo. Thus, we have established a powerful cross species in vivo platform capable of uncovering host genetic factors that establish the tumor immune microenvironment configuration propitious for ICI response.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Idioma: En Revista: BioRxiv Año: 2024 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Estados Unidos
Texto completo
Añadir a Mi BVS
Imprimir
XML
PubMed Links
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Idioma: En Revista: BioRxiv Año: 2024 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Estados Unidos