Dual mechanistic function of MDSC subsets in melanoma resistance.

Abstract

8590 Background: Myeloid-derived suppressor cells (MDSC) accumulate in tumor-bearing hosts, suppress T-cell function and promote tumor-driven angiogenesis. Melanoma represents a resistant tumor type that is nevertheless highly immunogenic. Angiogenesis, closely linked to ulceration in primary tumors, plays a particularly important role in melanoma progression. The role of MDSC in promoting immune suppression and angiogenesis in melanoma is not fully understood. Methods: T-cell function (IFNγ production), MDSC subset frequencies (CD15+ neutrophilic, n-MDSC, CD14+ monocytic, m-MDSC, and CD15-CD14- immature, i-MDSC) and MDSC production of proangiogenic factors were measured in stage III/IV melanoma patients. n-MDSC and m-MDSC were induced from healthy donor blood by melanoma conditioned media (MCM). Induced n-MDSC and m-MDSC were compared in their ability to impact growth and vascularity in melanoma xenografts. Results: T- cells derived from melanoma patients were significantly deficient in Type-1 function compared to those from age-matched healthy donors (5.91±0.9%,n = 15 versus 18.01±1.4%, n = 21 IFNγ+CD3+ p < 0.0000002), and this was linked to elevations in all MDSC subsets (1.66±0.37% n-MDSC p = 0.001, 1.51±0.20% i-MDSC p = 0.2, 0.14±.025% m-MDSC p = 0.015; 3.3±0.46 total-MDSC p = 0.01, n = 15) compared to healthy donors (0.19±0.14% n-MDSC, 1.12±0.36% i-MDSC, 0.06±.019% m-MDSC; 1.37±0.46 total-MDSC, n = 5). Proteome array showed patient- derived MDSC produced several proangiogenic factors (IL-8, MMP8/9, platelet factor and VEGF). MCM bestowed healthy donor-derived neutrophils and monocytes with phenotypic and functional n- and m-MDSC identities. Studies examining enhancement of growth and blood vessel formation in xenografted melanoma tumors by induced n- and m-MDSC are ongoing. Conclusions: Tumor-driven n-MDSC and m-MDSC induction diminishes the potential effectiveness of antitumor immunity and promotes angiogenesis in melanoma. Further identification of those factors involved in this induction, as well as strategies aimed at reversing MDSC in melanoma using drugs such as sunitinib, could have potential therapeutic impact in melanoma. No significant financial relationships to disclose.