Diversity Outbred and Collaborative Cross mouse models identify and validate host genetic Loci associated with Immune Checkpoint Inhibitor response

Abstract Immune checkpoint inhibitors (ICI) for cancer therapy have improved outcomes for a variety of malignancies, however many patients fail to benefit. While tumor-intrinsic mechanisms are involved in therapy resistance, it is unclear to what extent host genetic background plays in response. To investigate this in a pre-clinical setting, we utilized C57BL/6 (B6) F1 crosses of the Diversity Outbred (DO) and Collaborative Cross (CC) mouse models. We find a wide variation in response to anti-PD-1/anti-CTLA-4 ICI in B16F0-bearing DOB6F1 mice (n=142) with ~30% showing partial response and ~13% showing complete tumor elimination. Genetic linkage analysis identified several genomic loci associated with therapeutic outcomes. Of the associated loci, the region within chromosome 13 was further validated in CC mice bearing the positive (NZO) versus negative (C57BL/6) driver genotypes. ICI response was detected in 2/3 CCB6F1 predicted responder models, with no response in predicted non-responders. This locus contains the murine prolactin family which is a known immunomodulating cytokine with association to 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. Combined ICI with prolactin shows an interaction effect against B16F0, with 5/8 mice exhibiting slowed tumor growth. Analysis of CD8 infiltrates by IHC demonstrate that dual treatment of prolactin and ICI results in a significant increase of CD8 infiltrates over other groups. Collectively, this study shows that host genetics play a role in ICI response and that prolactin may be a positive regulator of ICI efficacy. Supported by grants from NIH (R37 CA220482, T32-CA009531, P30 CA022453), the Pardee Foundation, and the DMC Foundation