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Modak, M.* ; Mattes, A.K.* ; Reiss, D.* ; Skronska-Wasek, W.* ; Langlois, R.* ; Sabarth, N.* ; Konopitzky, R.* ; Ramírez, F.* ; Lehr, K.* ; Mayr, T.* ; Kind, D.* ; Viollet, C.* ; Swee, L.K.* ; Petschenka, J.* ; El Kasmi, K.C.* ; Nößner, E. ; Kitt, K.* ; Pflanz, S.*

CD206+ tumor-associated macrophages cross-present tumor antigen and drive anti-tumor immunity.

JCI insight 7:e155022 (2022)

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In many solid cancers, tumor-associated macrophages (TAM) represent the predominant myeloid cell population. Antigen (Ag) cross-presentation leading to tumor Ag-directed cytotoxic CD8+ T cell responses is crucial for anti-tumor immunity. However, the role of recruited monocyte-derived macrophages, including TAM, as potential cross-presenting cells is not well understood. Here, we show that primary human as well as mouse CD206+ macrophages are effective in functional cross-presentation of soluble self and non-self Ag, including tumor-associated Ag (TAA) as well as viral Ag. To confirm the presence of cross-presenting TAM in vivo, we performed phenotypic and functional analysis of TAM from B16-F10 and CT26 syngeneic tumor models and have identified CD11b+F4/80hiCD206+ TAM to effectively cross-present TAA. We show that CD11b+CD206+ TAM represent the dominant tumor-infiltrating myeloid cell population, expressing a unique cell surface repertoire, promoting Ag cross-presentation and Ag-specific CD8+ T cell activation comparable to cross-presenting CLEC9A+ dendritic cells (cDC1). The presence of cross-presenting CD206+ TAM is associated with reduced tumor burden in mouse syngeneic tumor models and with improved overall survival in cutaneous melanoma patients. Therefore, the demonstration of effective Ag cross-presentation capabilities of CD206+ TAM, including their clinical relevance, expands our understanding of TAM phenotypic diversity and functional versatility.

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