Data from Intratumoral CD16<sup>+</sup> Macrophages Are Associated with Clinical Outcomes of Patients with Metastatic Melanoma Treated with Combination Anti-PD-1 and Anti-CTLA-4 Therapy

<div>AbstractPurpose:<p>This study characterizes intratumoral macrophage populations within baseline melanoma biopsies from patients with advanced melanoma who received either anti-PD-1 monotherapy or a combination with anti-CTLA-4. Particularly, FcγRIIIa (CD16)-expressing macrophage densities were investigated for associations with response and progression-free survival.</p>Experimental Design:<p>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.</p>Results:<p>Patients who responded to combination immune checkpoint inhibitor contained higher CD16<sup>+</sup> macrophage densities than those who did not respond (196 vs. 7 cells/mm<sup>2</sup>; <i>P =</i> 0.0041). There was no diffidence in CD16<sup>+</sup> macrophage densities in the PD-1 monotherapy-treated patients based on response (118 vs. 89 cells/mm<sup>2</sup>; <i>P</i> = 0.29). A significantly longer 3-year progression-free survival was observed in combination-treated patients with high intratumoral densities of CD16<sup>+</sup> macrophages compared with those with low densities (87% vs. 42%, <i>P</i> = 0.0056, <i>n</i> = 40). No association was observed in anti-PD-1 monotherapy-treated patients (50% vs. 47%, <i>P</i> = 0.4636, <i>n</i> = 50). Melanoma biopsies with high densities of CD16<sup>+</sup> macrophages contained upregulated gene expression of critical T-cell recruiting chemokines (<i>CXCL9</i>, <i>CXCL10</i>, and <i>CXCL11</i>).</p>Conclusions:<p>Our data demonstrate that tumor microenvironments enriched with CD16<sup>+</sup> 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.</p></div>