Abstract B50: Discovery of multiple mechanisms of immune evasion that accelerate primary melanomagenesis in a genetic model with low tumor mutation burden


 Although immune checkpoint blockade (ICB) therapy can improve outcomes in advanced melanoma, early detection and treatment focused on preventing metastasis remain the optimal approaches for superior survival. Immune evasion occurs early in melanoma development and as such, some patients with high-risk Stage II (nonmetastatic) disease benefit from ICB. These human data highlight a critical need to understand the complex process of immune evasion during melanoma formation and early progression. To this end, we interrogated the tumor immune microenvironment of the RCAS-CRE inducible, Dct::TVA; BrafV600E; Cdkn2aNull murine model of melanoma. Tumor development occurs rapidly and at high frequency in these mice, without exposure to ultraviolet light or mutagenic carcinogens, modeling an important molecular class of melanoma with low mutation burden, which generally occurs in young patients. Using single-cell RNA sequencing and immunostaining, we discovered that primary tumors show evidence of an adaptive immune response that is restricted by myeloid-derived suppressor cells, regulatory T cells and PD-L1 expression. Systemic anti-PD-1 treatment reduced tumor incidence and significantly delayed tumor onset. Despite the low mutation burden, our data demonstrate the presence of a smoldering adaptive immune response that can be unleashed with ICB to limit tumor formation. Importantly, unlike syngeneic allograft models, our genetic model provides a unique opportunity to interrogate tumor-intrinsic mechanisms of immune evasion during an auspicious time window that spans from - tumor initiation to high-risk, pre-metastatic disease. Thus, we have identified a useful in vivo tool for the discovery of novel mechanisms of immune evasion and for testing therapeutic interventions in early-stage disease.
 Citation Format: Emily C Wilson, Yinshen Wee, Junhua Wang, Coulson P Rich, Aaron Rogers, Roger K Wolff, Sheri L Holmen, Allie H Grossmann. Discovery of multiple mechanisms of immune evasion that accelerate primary melanomagenesis in a genetic model with low tumor mutation burden [abstract]. In: Proceedings of the AACR Special Conference: Tumor Immunology and Immunotherapy; 2022 Oct 21-24; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2022;10(12 Suppl):Abstract nr B50.