Immune checkpoint inhibitors (ICPi; e.g. anti-CTLA-4, anti-PD-1, anti-PD-L1) have shown great promise for melanoma treatment; however, sustained responses are achieved only in a fraction of patients, while the majority does not respond at all. Though load and patterns of mutations have been shown to be associated with IMT responses, the determinants have never been well characterized. In this study we aimed to identify predictive markers of melanoma response to ICPi by preclinical modeling. Three genetically engineered mice (GEM) were built to model melanomagenesis driven by different carcinogenic processes: (1) UV in albino BRAF(V600E); PTEN-knockout C57BL/6 mice, (2) carcinogen DMBA in pigmented Hgf-tg; CDK4(R24C) C57BL/6 mice, and (3) UV in pigmented Hgf-tg C57BL/6 mice. Melanoma cells derived from these models were subjected for exome sequencing and immunogenicity test by vaccination and challenge. Their responses to anti-CTLA-4 antibody were then tested in preclinical settings. Model (1), (2) and (3) are non-, medium-, and high-immunogenic, respectively. Consistent with published data, responses to anti-CTLA-4 are well correlated with the immunogenicity of individual melanoma models. Moreover, co-administration of BRAF or MEK inhibitors with immunotherapy did not enhance therapeutic efficacy. Based on exome sequencing, all the models exhibit coding mutations in genes of neuronal development, MAPK pathways, and G protein-coupled pathways, but UV-type mutations (C to T and G to A) were enriched only in model (1). Interestingly, deleterious mutations in DNA damage response (DDR) genes existed only in immunogenic models (2) and (3). These results suggested that carcinogenic mechanisms determine tumor immunogenicity and therefore response to IMT. Consistent with recent data from clinical studies, mutations in DDR genes may be predictive of IMT response. Currently we are evaluating the functions of specific DDR genes in melanoma, and the possibility they may serve as therapeutic targets in combination therapies with ICPi.
Citation Format: Chi-Ping Day, Rajaa El Meskini, Cari Graff-Cherry, Aleksandra Michalowski, Zoe Weaver Ohler, Terry Van Dyke, Glenn Merlino. Identifying determinants of melanoma response to immune checkpoint inhibitors via preclinical modeling. [abstract]. In: Proceedings of the CRI-CIMT-EATI-AACR Inaugural International Cancer Immunotherapy Conference: Translating Science into Survival; September 16-19, 2015; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2016;4(1 Suppl):Abstract nr B112.
- ©2016 American Association for Cancer Research.