Modak et al. found that human monocyte-derived macrophages (MDM) capably cross- presented soluble (melanoma TyrD peptide or cytomegalovirus protein), but not intact cell antigens to CD8+ T cells. Although both MDM subtypes internalized antigen, CD206+ M2a MDM cross-presented more effectively than M1 or M2c MDM, and expressed higher ICOSLG and lower PD-L1 than M1 MDM. CD206+ macrophages were enriched in slow-growing (vs. rapid) B16F10 tumors, and were associated with antigen-specific CD8+ T cell activity. In melanoma and retinal cell carcinoma patient data from TCGA, CD206 expression correlated with OS.
Contributed by Alex Najibi
ABSTRACT: 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.