High-motility pro-tumorigenic monocytes drive macrophage enrichment in the tumor microenvironment

• Published in: bioRxiv
• Main Authors: Du, Wenxuan, Zhou, Bryan, Forjaz, André, Shin, Sarah M, Wu, Fan, Crawford, Ashleigh J, Nair, Praful R, Johnston, Adrian C, West-Foyle, Hoku, Tang, Ashley, Kim, Dongjoo, Fan, Rong, Kiemen, Ashley L, Wu, Pei-Hsun, Phillip, Jude M, Ho, Won Jin, Sanin, David E, Wirtz, Denis
• Format: Journal Article
• Language: English
• Published: United States 18.07.2024
• ISSN: 2692-8205; 2692-8205
• DOI: 10.1101/2024.07.16.603739

Enrichment of tumor-associated macrophages (TAMΦs) in the tumor microenvironment correlates with worse clinical outcomes in triple-negative breast cancer (TNBC) patients, prompting the development of therapies to inhibit TAMΦ infiltration. However, the lackluster efficacy of CCL2-based chemotaxis blockade in clinical trials suggests that a new understanding of monocyte/macrophage infiltration may be necessary. Here we demonstrate that random migration, and not only chemotaxis, drives macrophage tumor infiltration. We identified tumor- associated monocytes (TAMos) that display a dramatically enhanced migration capability, induced rapidly by the tumor microenvironment, that drives effective tumor infiltration, in contrast to low-motility differentiated macrophages. TAMo, not TAMΦ, promotes cancer cell proliferation through activation of the MAPK pathway. IL-6 secreted both by cancer cells and TAMo themselves enhances TAMo migration by increasing dendritic protrusion dynamics and myosin- based contractility via the JAK2/STAT3 signaling pathway. Independent from CCL2 mediated chemotaxis, IL-6 driven enhanced migration and pro-proliferative effect of TAMo were validated in a syngeneic TNBC mouse model. Depletion of IL-6 in cancer cells significantly attenuated monocyte infiltration and reversed TAMo-induced cancer cell proliferation. This work reveals the critical role random migration plays in monocyte driven TAMΦ enrichment in a tumor and pinpoints IL-6 as a potential therapeutic target in combination with CCL2 to ameliorate current strategies against TAMΦ infiltration.