journal contribution posted on 2023-07-05, 08:23 authored by Hansol Lee, Angela L. Ferguson, Camelia Quek, Ismael A. Vergara, Ines Pires daSilva, Ruth Allen, Tuba Nur Gide, Jordan W. Conway, Lambros T. Koufariotis, Nicholas K. Hayward, Nicola Waddell, Matteo S. Carlino, Alexander M. Menzies, Robyn P.M. Saw, Elena Shklovskaya, Helen Rizos, Serigne Lo, Richard A. Scolyer, Georgina V. Long, Umaimainthan Palendira, James S. Wilmott
C1Q and PD-1 expression on CD16+ macrophages in on treatment biopsies of melanoma patients treated with PD-1 or PD-1+CTLA-4 ICB. Dynamics between pretreatment and early-during treatment biopsies on (a) CD16+ macrophages as a proportion of all macrophages (b) CD16+ C1q+ macrophages as a proportion of all C1q+ macrophages (c) PD-1+ CD16+ macrophages as a proportion of PD-1+ macrophages (d) PD-1+ CD16+ C1q+ macrophages as a proportion of all macrophages (e) C1q+ CD16+ macrophages as a proportion of CD16+ macrophages (f) PD-1+ CD16+ macrophages as a proportion of CD16+ macrophages. (g) Log2 RNA expression of C1qa-c in pretreatment (PRE) and early during treatment (EDT) biopsies of responding and non-responding patients treated with PD-1 or PD-1+CTLA-4 ICB. (h) Flow cytometry analysis of ipilimumab (IgG1) and/or secondary anti-IgG1 binding to CD16+ and CD16- macrophages in a melanoma patient's tumor dissociate. FMO, a no-secondary control.
National Health and Medical Research Council (NHMRC)
Melanoma Research Alliance (MRA)
Cancer Institute NSW (Cancer Institute New South Wales)
Cancer Council NSW (Cancer Council New South Wales)
ARTICLE ABSTRACTThis 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.
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.
Patients who responded to combination immune checkpoint inhibitor 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 significantly longer 3-year progression-free survival was observed in combination-treated patients with high intratumoral densities of CD16+ 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+ macrophages contained upregulated gene expression of critical T-cell recruiting chemokines (CXCL9, CXCL10, and CXCL11).
Our data demonstrate that tumor microenvironments enriched with CD16+ 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