Intratumoral CD16+ macrophages are associated with clinical outcomes of patients with metastatic melanoma treated with combination anti-PD-1 and anti-CTLA-4 therapy.

Lee H, Ferguson AL, Quek C, Vergara IA, Pires daSilva I, Allen R, Gide TN, Conway JW, Koufariotis LT, Hayward NK, Waddell N, Carlino MS, Menzies AM, Saw RPM, Shklovskaya E, Rizos H, Lo S, Scolyer RA, Long GV, Palendira U, Wilmott JS. Clin Cancer Res. 2023 Feb 15:CCR-22-2657. doi: 10.1158/1078-0432.CCR-22-2657. Epub ahead of print. PMID: 36790412.


Purpose: This study characterizes intratumoural macrophage populations within baseline melanoma biopsies from patients with advanced melanoma who received either anti-PD-1 monotherapy or combination with anti-CTLA-4. Particularly, FcγRIIIa (CD16) expressing macrophage densities were investigated 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 immunohistochemistry in relation to treatment outcomes.

Results: Patients who responded to combination ICI contained higher CD16+ macrophage densities than those who did not respond (196 vs 7 cells/mm2; p = 0.0041). There was no diffidence in CD16+ macrophage densities in the PD-1 monotherapy-treated patients based on response (118 vs 89 cells/mm2; p = 0.29). A significant longer 3-year progression-free survival was observed in combination treated patients with high intratumoral densities of CD16+ macrophages compared to 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+ macrophages contained upregulated gene expression of critical T-cell recruiting chemokines (CXCL9, CXCL10 and CXCL11).

Conclusion: Our data demonstrates that tumor environments enriched with CD16+ macrophages are favorable for response to combination anti-PD-1 and anti-CTLA-4 therapy but not anti-PD-1 monotherapy. This data provides a potential biomarker of response for combination immunotherapies in patients with metastatic melanoma.