Abstract 420: The role of tumor microenvironment in therapy resistance and melanoma progression

Abstract

Abstract Melanoma patients develop resistance to both chemo- and targeted-therapy drugs. Promising pre-clinical and clinical results with immune checkpoint inhibitors using antibodies directed against CTLA4 and PD1 have re-energized the field of immune-based therapies in melanoma. However, similar to chemo- or targeted-therapies only subsets of melanoma patients respond to immune checkpoint blockade. Studies from our laboratory have indicated that the tumor microenvironment (TME) might play a role in the emergence of therapy resistant tumor subpopulations. The TME actively recruits a number of immune and non-immune cells. A recent study describes immune cells as an important component of TME. About 33% of the infiltrating immune cells are of ‘B-cell’ lineage and yet, there is very little information on the role of these cells in melanoma cell biology. Our results suggest that B cells isolated from the tumor tissues of melanoma patients show higher inflammatory cytokine expressions (IGF-1, IL-1, PDGF and VEGF) when compared to circulating B cells. Presence of inflammatory cytokines in the TME results in the induction of heterogeneous melanoma subpopulation, down modulation of melanoma associated antigens (MAA), and thus, therapy resistance of melanoma. Here, we report a novel mechanism of acquired drug resistance in melanoma induced by tumor-associated B cells involving FGF-2/FGFR-3 and IGF-1 signaling. B-cell derived IGF-1 modulates the emergence of therapy resistant heterogeneous melanoma subpopulations. Neutralization of IGF-1 reverses the induction of heterogeneous melanoma subpopulations. We are currently evaluating the mechanism of down modulation of MAA in presence of inflammatory cytokines. Our studies confirm the important role of the TME in the induction of therapy resistant tumor subpopulations and offer a new combination treatment approach of targeting melanoma (Supported by AMRF and NIH grant CA114046). Citation Format: Rajasekharan Somasundaram, Gao Zhang, Stephan N. Wagner, Mizuho Fukunaga-Kalabis1, Meenhard Herlyn. The role of tumor microenvironment in therapy resistance and melanoma progression. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 420. doi:10.1158/1538-7445.AM2015-420