A diversity outbred F1 mouse model identifies host-intrinsic genetic regulators of response to immune checkpoint inhibitors.
Immune checkpoint inhibitor
collaborative cross
diversity outbred
genetic linkage analysis
immunotherapy resistance
melanoma
prolactin
Journal
Oncoimmunology
ISSN: 2162-402X
Titre abrégé: Oncoimmunology
Pays: United States
ID NLM: 101570526
Informations de publication
Date de publication:
2022
2022
Historique:
entrez:
28
4
2022
pubmed:
29
4
2022
medline:
30
4
2022
Statut:
epublish
Résumé
Immune checkpoint inhibitors (ICI) have improved outcomes for a variety of malignancies; however, many patients fail to benefit. While tumor-intrinsic mechanisms are likely involved in therapy resistance, it is unclear to what extent host genetic background influences response. To investigate this, we utilized the Diversity Outbred (DO) and Collaborative Cross (CC) mouse models. DO mice are an outbred stock generated by crossbreeding eight inbred founder strains, and CC mice are recombinant inbred mice generated from the same eight founders. We generated 207 DOB6F1 mice representing 48 DO dams and demonstrated that these mice reliably accept the C57BL/6-syngeneic B16F0 tumor and that host genetic background influences response to ICI. Genetic linkage analysis from 142 mice identified multiple regions including one within chromosome 13 that associated with therapeutic response. We utilized 6 CC strains bearing the positive (NZO) or negative (C57BL/6) driver genotype in this locus. We found that 2/3 of predicted responder CCB6F1 crosses show reproducible ICI response. The chromosome 13 locus contains the murine prolactin family, which is a known immunomodulating cytokine associated with various autoimmune disorders. To directly test whether prolactin influences ICI response rates, we implanted inbred C57BL/6 mice with subcutaneous slow-release prolactin pellets to induce mild hyperprolactinemia. Prolactin augmented ICI response against B16F0, with increased CD8 infiltration and 5/8 mice exhibiting slowed tumor growth relative to controls. This study highlights the role of host genetics in ICI response and supports the use of F1 crosses in the DO and CC mouse populations as powerful cancer immunotherapy models.
Identifiants
pubmed: 35481286
doi: 10.1080/2162402X.2022.2064958
pii: 2064958
pmc: PMC9037414
doi:
Substances chimiques
Immune Checkpoint Inhibitors
0
Prolactin
9002-62-4
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
2064958Subventions
Organisme : NCI NIH HHS
ID : P30 CA022453
Pays : United States
Organisme : NCI NIH HHS
ID : R37 CA220482
Pays : United States
Organisme : NCI NIH HHS
ID : T32 CA009531
Pays : United States
Informations de copyright
© 2022 The Author(s). Published with license by Taylor & Francis Group, LLC.
Déclaration de conflit d'intérêts
No potential conflict of interest was reported by the author(s).
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