Intratumoral CD16± Macrophages Are Associated with Clinical Outcomes of Patients with Metastatic Melanoma Treated with Combination Anti-PD-1 and Anti-CTLA-4 Therapy

Purpose: This study characterizes intratumoral macrophage populations within baseline melanoma biopsies from patients with advanced melanoma who received either anti-PD-1 mono-therapy or a combination with anti-CTLA-4. Particularly, FcyRIIIa (CD16)-expressing macrophage densities were inves-tigated for associations with response and progression-free survival.Experimental Design: Patients with advanced melanoma who received either anti-PD-1 monotherapy or combination anti-PD-1 and anti-CTLA-4 were retrospectively identified. Macrophage populations were analyzed within baseline melanoma biopsies via multiplex IHC in relation to treatment outcomes.Results: Patients who responded to combination immune checkpoint inhibitor contained higher CD16 & PLUSMN; macrophage densities than those who did not respond (196 vs. 7 cells/mm2; P = 0.0041). There was no diffidence in CD16 & PLUSMN; macrophage densities in the PD-1 monotherapy-treated patients based on response (118 vs. 89 cells/mm2; P = 0.29). A significantly longer 3-year progression-free survival was observed in combination-treated patients with high intratumoral densities of CD16 & PLUSMN; macrophages compared with those with low densities (87% vs. 42%, P = 0.0056, n = 40). No association was observed in anti-PD-1 monotherapy-treated patients (50% vs. 47%, P = 0.4636, n = 50). Melanoma biopsies with high densities of CD16 & PLUSMN; macrophages contained upregulated gene expression of critical T-cell recruiting chemokines (CXCL9, CXCL10, and CXCL11). Conclusions: Our data demonstrate that tumor microenviron-ments enriched with CD16 & PLUSMN; macrophages are favorable for response to combination anti-PD-1 and anti-CTLA-4 therapy but not anti-PD-1 monotherapy. These data provides a potential biomarker of response for combination immunotherapies in patients with metastatic melanoma. See related commentary by Smithy and Luke, p. 2345

Automated summary

This study characterized intratumoral macrophage populations in melanoma biopsies and investigated the association between CD16-expressing macrophage densities and treatment outcomes for patients receiving anti-PD-1 monotherapy or a combination with anti-CTLA-4. The results showed that patients who responded to combination therapy had higher CD16 macrophage densities compared to those who did not respond. Additionally, patients with high intratumoral densities of CD16 macrophages had a significantly longer progression-free survival. These findings suggest that CD16 macrophages may serve as a potential biomarker for response to combination immunotherapies in metastatic melanoma patients.