BackgroundThe immune checkpoint inhibitors (ICIs) revolutionized cancer therapeutic landscape and substantially improved the survival of patients (pts) with advanced malignancies, especially in skin cancer pts.1–5 IL-6 is a key inflammatory molecule secreted by M2 macrophages after polarization, mediating the progression of pancreatic and colorectal cancer.6 7 The purpose of this study is to retrospectively investigate the relationships between IL-6 and outcome in skin cancer patients treated with immunotherapy.MethodsIL-6 levels were analyzed in two independent cohorts, in cohort 1 serum IL-6 were evaluated from 386 consecutive skin cancer pts before start ICIs. We included pts with unresectable/metastatic cutaneous squamous cell carcinoma (cSCC) treated with cemiplimab (n=47); pts with resected stage III/IV melanoma (n=98) treated with anti-PD1; pts with metastatic melanoma treated with anti-PD1 (n=139), combo ipi+nivo (n=65) and ipilimumab alone (n=37). IL-6 was measured by Electrochemiluminescence immunoassays (ECLIA) from Cobas C6000 (Roche). In cohort 2 we conducted a gene profile analysis with Nanostring from PBMCs of 121 metastatic melanoma pts. All pts signed informed consent. Patient’s characteristics are listed in table 1. ROC curves were used to determine the best cut off. Survival rates were analyzed using the Kaplan-Meier method. Hazard Ratios (HR) and their 95% confidence intervals (CI) were estimated using a Cox regression model.ResultsAmong 507 pts, in cohort 1 lower serum IL-6 was associated with a better Progression Free Survival (PFS) 18.67 months (95% CI 16.6–20.7) versus 10.31 months (95% CI 8.5–12.0), HR = 0.45 (CI 0,3–0,5, p<0.0001); Overall Survival (OS) (27.59 months (95% CI 25.9–29.2) versus 20.12 months (95% CI 17.7–22.4), HR = 0.32 (CI 0,23–0,47, p<0.0001) and Overall Response Rate (ORR) (p<0.001). Similarly, IL-6 and previous therapy are associated with OS and PFS in multivariate analysis (p <0.01). We also confirmed the association between IL-6 and outcomes in all subgroups. In cohort 2 we observed a similar trend in pts with lower IL-6 expression. Moreover, higher IL-6 was associated to MAP3K12, EGFR, SELL,FPR1 genes.ConclusionsWe found that lower levels of both serum and gene expression of IL-6 are associated with better OS, PFS and ORR. Furthermore, IL-6 is associated to higher expression of genes relate to cell cycle, proliferation and metastasis. Further investigations are needed to get additional information.AcknowledgementsThis work was supported by the Italian Ministry of Health Ricerca Corrente fundsReferencesJames Larkin, Vanna Chiarion-Sileni, Rene Gonzalez, Jean Jacques Grob, C Lance Cowey et al. Combined Nivolumab and Ipilimumab or Monotherapy in Untreated Melanoma. N Engl J Med. 2015 Jul 2;373(1):23–34.Robert C, Long GV, Brady B, Dutriaux C, Maio M, et al. Nivolumab in previously untreated melanoma without BRAF mutation. N Engl J Med. 2015 Jan 22;372(4):320–30.Weber JS, D’Angelo SP, Minor D, Hodi FS, Gutzmer R. Nivolumab versus chemotherapy in patients with advanced melanoma who progressed after anti-CTLA-4 treatment (CheckMate 037): a randomised, controlled, open-label, phase 3 trial. Lancet Oncol. 2015 Apr;16(4):375–84.Schenker M, Chiarion-Sileni V, Marquez-Rodas I, Grob JJ, Butler MO, et al. CheckMate 238 Collaborators. Adjuvant Nivolumab versus Ipilimumab in Resected Stage III or IV Melanoma. N Engl J Med. 2017 Nov 9;377(19):1824–1835.Larkin J, Chiarion-Sileni V, Gonzalez R, Grob JJ, Cowey CL, et al. Combined Nivolumab and Ipilimumab or Monotherapy in Untreated Melanoma. N Engl J Med. 2015 Jul 2;373(1):23–34.He Z, Wang J, Zhu C, Xu J, Chen P, Jiang X, et al. Exosome-derived FGD5-AS1 promotes tumor-associated macrophage M2 polarization-mediated pancreatic cancer cell proliferation and metastasis. Cancer Lett 2022;548:215751. doi: 10.1016/j.canlet.2022.215751.Li W, Wu Z, Meng W, Zhang C, Cheng M, Chen Y, et al. Blockade of IL-6 inhibits tumor immune evasion and improves anti-PD-1 immunotherapy. Cytokine. 2022;158:155976. doi: 10.1016/j.cyto.2022.155976.Ethics ApprovalThis study was approved by the Ethics Committee of National Cancer Institute—IRCCS—Fondazione ‘‘G. Pascale’’, Naples, Italy, protocol number 32/22 oss. All patients provided their written informed consent to participate in this study.ConsentWritten informed consent was obtained from the patient for publication of this abstract and any accompanying images. A copy of the written consent is available for review by the Editor of this journal.Abstract 42 Table 1