Tumor-Associated Macrophages Promote Invasion while Retaining Fc-Dependent Anti-Tumor Function

Abstract

Tumor-associated macrophages (TAMs) have been shown to promote tumor progression, and increased TAM infiltration often correlates with poor prognosis. However, questions remain regarding the phenotype of macrophages within the tumor and their role in mAb-dependent cytotoxicity. This study demonstrates that whereas TAMs have protumor properties, they maintain Fc-dependent anti-tumor function. CD11b+CD14+ TAMs isolated from primary human breast tumors expressed activating FcγRs. To model breast cancer TAMs in vitro, conditioned medium from breast cancer cells was used to drive human peripheral monocyte differentiation into macrophages. Tumor-conditioned macrophages were compared with in vitro derived M1 and M2a macrophages and were found to promote tumor cell invasion and express M2a markers, confirming their protumor potential. However, unlike M2a macrophages, tumor-conditioned macrophages expressed FcγRs and phagocytosed tumor cells in the presence of a tumor Ag-targeting mAb, unmasking an underappreciated tumoricidal capacity of TAMs. In vivo macrophage depletion reduced the efficacy of anti-CD142 against MDA-MB-231 xenograft growth and metastasis in SCID/beige mice, implicating a critical role for macrophages in Fc-dependent cell killing. M-CSF was identified in tumor-conditioned media and shown to be capable of differentiating macrophages with both pro- and anti-tumor properties. These results highlight the plasticity of TAMs, which are capable of promoting tumor progression and invasion while still retaining tumoricidal function in the presence of tumor-targeting mAbs.

GDF15 derived from both tumor-associated macrophages and esophageal squamous cell carcinomas contributes to tumor progression via Akt and Erk pathways

“…Recent studies have shown that TAM-like PBMo-derived macrophages stimulated with TCM such as those found in breast, ovarian, and colorectal cancer produced these factors. 16,[38][39][40] In the present study, GDF15 was upregulated in PBMo-derived macrophages stimulated with TECM, whereas, to our knowledge, it has not been reported that TAM-like PBMo-derived macrophages stimulated with other TCMs secreted GDF15. Expression of GDF15 was not detected in cytokine-induced M2-polarized macrophages such as IL-4 and IL-13 (Supplementary Figure 1).…”

Antibody-mediated phagocytosis contributes to the anti-tumor activity of the therapeutic antibody daratumumab in lymphoma and multiple myeloma

“…4 Furthermore, these mw may protect MM cells from chemotherapy drug-induced apoptosis. 5 Remarkably, tumor-associated mw may still induce Fc-dependent anti-tumor activity, 40 supporting a role for DARA-induced phagocytosis in the BM. Another approach is the combination with drugs regulating anti-phagocytic signals.…”

Immune-mediated mechanisms influencing the efficacy of anticancer therapies

“…antibodies is reversed [109][110][111][112][113][114][115]. A lymphoma patient study showing that high TAM infiltration correlates with improved prognosis after a rituximab-containing regimen, but worsened prognosis without rituximab, supports these observations [116].…”