Abstract A117: Tumor-produced IL-6 and IL-8 are associated with MDSC accumulation and correlate with long-term clinical outcomes in melanoma patients
Authors: Tobin Richard P. , Jordan Kimberly R. , Davis Dana , Vorwald Victoria M. , Couts Kasey , Gao Dexiang , Smith Derek E , Robinson William A , Borges Virginia , McCarter Martin D 
Published: February 2019

Abstract
Background: Recruitment and expansion of immunosuppressive myeloid cells present a significant barrier to the successful treatment of melanoma. We aimed to identify tumor-secreted factors that altered the frequency of MDSCs and correlated with clinical outcomes in advanced melanoma patients. We hypothesized that production of IL-6 and IL-8 by melanoma tumors would lead to expansion and accumulation of MDSCs and correlate with long-term clinical outcomes. Methods: Expression of IL-6 and IL-8 in melanoma tumors as well as the plasma concentration of IL-6 and IL-8 were measured and compared with the frequency of circulating MDSCs in a total of 52 stage IV melanoma patients. These measures were correlated with tumor burden, BRAF status, lactic acid dehydrogenase (LDH) levels and with clinical outcomes. Samples were collected beginning in January 2011 and clinical follow-up was collected through January 2018. Results: The plasma concentration of both IL-6 and IL-8 correlated with tumor burden (p &lt; 0.0001 and p= 0.0122, respectively). Patients with high plasma concentrations of either IL-6 (40%) or IL-8 (63%) had worse median overall survival (MOS) (7.5 months, p &lt; 0.0001 and 9.2 months, p = 0.0015, respectively) compared to patients with low concentrations, where MOS was not reached. Patients with high plasma concentrations of both IL-6 and IL-8 (35%) had even worse MOS (6.7 months) than patients with low levels of both cytokines (MOS not reached, 31%) p &lt; 0.0001. We observed that patients with lower circulating concentrations and lower tumoral expression of IL-6 and IL-8 showed decreased frequencies of circulating MDSCs. Furthermore, patients with low frequencies of MDSCs (MOS not reached) had better overall survival than patients with high frequencies of these cells (MOS 11.9 months) p = 0.0224. Multivariable analysis showed that when adjusting for variables BRAF status and LDH in the model, the hazard for the event of death for subjects with both high IL-6 and IL-8 is 4.46 times (95% CI, 1.4, 14.2) that of the hazard for the subjects with low IL-6 and IL-8 (p = 0.01). Additionally, the hazard of death for subjects with higher total MDSCs is 3.3 times (95% CI, 1.2, 9.0) that for subjects with low total MDSCs. Conclusions: The durability of the nearly 7-year follow-up time for these advanced melanoma patients further strengthens the implied importance of IL-6 and IL-8 in the accumulation of MDSC’s in melanoma patients. These data provide clues for potential therapeutic targets in advanced melanoma patients.
Citation Format: Richard P. Tobin, Kimberly R. Jordan, Dana Davis, Victoria M. Vorwald, Kasey Couts, Dexiang Gao, Derek E Smith, William A Robinson, Virginia Borges, Martin D McCarter. Tumor-produced IL-6 and IL-8 are associated with MDSC accumulation and correlate with long-term clinical outcomes in melanoma patients [abstract]. In: Proceedings of the Fourth CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; Sept 30-Oct 3, 2018; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2019;7(2 Suppl):Abstract nr A117.