Cutaneous squamous cell carcinoma (cuSCC) accounts for 15-20% of skin cancers. Treatment of cuSCC with pramlintide, a synthetic analog of the hormone amylin, is currently under investigation in mouse models and human clinical trials. In cancer cells, pramlintide inhibits glycolysis, resulting in cell death and tumor regression. In order to investigate the potential use of pramlintide in combinatory therapies with checkpoint inhibitors, we aimed to study the immune modulatory effect of pramlintide in an immune competent mouse model of spontaneous ultraviolet radiation-induced cuSCC, as well as its effect on human T cells in vitro. To induce cuSCC, SKH-1 hairless mice were subjected to ultraviolet radiation until at least one tumor reached >4mm of diameter. Mice were then treated with 45 µg/kg of pramlintide or vehicle control for 10 days, every other day. Skin-draining lymph nodes, spleen and tumors were harvested for immunophenotyping of the T cell and myeloid compartment by flow cytometry. While the proportion of CD103+ dendritic cells (DCs) and CD3+ T cells remained constant after pramlintide treatment, a significant decrease in the proportion of both monocytic and granulocytic myeloid-derived suppressor cells (m-MDSCs and g-MDSCs) was observed relative to vehicle-control treated mice. Interestingly, pramlintide abolished m-MDSC differentiation from bone marrow progenitors in vitro suggesting that pramlintide may regulate a pathway necessary for m-MDSC development. Purified human CD3+ T cells activated in the presence of pramlintide exhibited a time-dependent increase in intracellular and secreted IFN-γ. Therefore, pramlintide may have immune modulatory effects based on both a reduction in myeloid-dependent suppression and a direct stimulatory effect on T cells that would culminate in superior anti-tumor T cell responses that augment immunotherapeutic approaches for the treatment of cuSCC.
Citation Format: Leticia Tordesillas, Rebecca Hesterberg, Ivannie Ortiz-Rivera, Brittney R. Sell, Omar Chavez Chiang, Kimberly T. Nguyen, Brian L. Murphy, Pearlie K. Burnette, Elsa R. Flores, Kenneth Y. Tsai. Immune modulatory effect of pramlintide for cutaneous squamous cell carcinoma treatment [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 1227.