Targeting CD206+ macrophages disrupts the establishment of a key anti-tumor immune axis [scRNA-seq]

CD206 is a common marker of a putative immunosuppressive ‘M2’ state in tumor-associated macrophages (TAMs). We made a novel conditional CD206 (Mrc1) knock-in mouse to specifically visualize and/or deplete CD206+ TAMs. Early depletion of CD206+ macrophages and monocytes (Mono/Macs) led to the indirect loss of conventional type I dendritic cells (cDC1), CD8 T cells and NK cells in tumors. CD206+ TAMs robustly expressed CXCL9, contrasting with stress-responsive Spp1-expressing TAMs and immature monocytes, which became prominent with early depletion. CD206+ TAMs differentially attracted activated CD8 T cells, and the NK and CD8 T cells in CD206-depleted tumors were deficient in Cxcr3, and cDC1-supportive Xcl1 and Flt3l expression. Disrupting this key anti-tumor axis decreased tumor control by antigen-specific T cells in mice. In human cancers, a CD206Replete, but not a CD206Depleted Mono/Mac gene signature correlated robustly with CD8 T cell, cDC1 and NK signatures, and associated with better survival. These findings negate the unqualified classification of CD206+ ‘M2-like’ macrophages as immunosuppressive. CD2dsRedOT-I CD8 T cells were adoptively transferred into Csf1rCre; Mrc1-LSL-Venus-DTR mice bearing B78chOVA tumors. 12d after T cell injection with or without early depletion by DTx administration every 2-3 days, tumors were isolated, sliced and prepared for spatial barcoding. Three zones - outer, mid, inner were barcoded by the localization of Venus, dsRed and SHG signals and spatial transcriptomics performed by ZipSeq using a anti-CD45 anchor. Samples listed here include the DTx treated group only while the untreated control group samples are included in an earlier GEO submission id # GSE201074