Abstract 4622: The YUMMER.G mouse melanoma model recapitulates the heterogeneous response to immune checkpoint blockade based on patient sex

Abstract

Abstract Existing murine melanoma models, such as syngeneic transplantation of the B16 melanoma cell line, are aggressive, but poorly immunogenic, and as a result, studying the response to immunotherapy in these models has been challenging. Furthermore, in humans, a heterogeneous response to immune checkpoint inhibitor therapy has been observed between male and female melanoma patients, yet no immunogenic murine cancer model exists to study this sex-related dimorphism. To address these challenges, we created the YUMMER.G model, a melanoma cell line driven by human-relevant Braf activation and loss of Pten and Cdkn2a. YUMMER.G is related to the previously described YUMMER1.7 model; however important differences include: diploid state, female genotype, and Mc1re/e (pheomelanin producing) background. YUMMER.G was created by treatment with UV-light, resulting in a neoantigen rich subclone. Subcutaneous injection of 2 million YUMMER.G cells into C57BL/6J mice resulted in melanoma formation in both male and female mice. Treatment of established tumors with anti-CTLA-4 resulted in a comparable response between male and female mice, with complete, durable tumor regression in 100% of female mice and 88% of male mice. However, when established YUMMER.G tumors were treated with anti-PD-1, 63% of female mice, but only 13% of male mice exhibited complete tumor regression (p = 0.0330). These findings demonstrate the important role of host sex in the response to immunotherapy, and they parallel the sex-related differences in checkpoint inhibitor efficacy that have been observed in human patients. In summary, the YUMMER.G model is a human-relevant, immunogenic mouse melanoma model that will serve as a valuable platform for further investigating the mechanisms that mediate the sex-related dimorphism in anti-tumor immunity and response to immunotherapy. Citation Format: Julie Y. Ramseier, Alexandra Charos, Koonam Park, William Damsky, Marcus W. Bosenberg. The YUMMER.G mouse melanoma model recapitulates the heterogeneous response to immune checkpoint blockade based on patient sex [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4622.