Nature 580, 257–262 (2020).

Antigen presentation by intratumoral conventional dendritic cells (cDCs) activates effector T cells to boost antitumor immunity upon checkpoint blockade therapy. Yet some tumors resist such therapy, despite the presence of cDCs, prompting the question of whether the tumor-resident cDCs are altered. In Nature, Maier et al. utilize single-cell RNA sequencing and CITE-seq (cellular indexing of transcriptomes and epitopes by sequencing) to identify a unique cDC subset, dubbed mregDCs, that express CD40, interleukin (IL)-12 and abundant major histocompatibility complex II (MHC-II) molecules, as well as immunoregulatory molecules that include PD-L1, CD274 and CD200. The mregDCs are distinct from previously described cDC1 and cDC2 subsets but appear to be derived from both subsets within the tumor environment. A similar mregDC subset is found in human lung tumors. Uptake of apoptotic cells within the tumor environment via recognition by the receptor tyrosine kinase molecule AXL induces mregDC formation, and these cells were more efficient at promoting Foxp3 expression in CD4+ T cells during in vitro coculture. The AXL signaling pathway is also necessary for upregulation of PD-L1 expression; however, it is not needed for IL-12 expression in mregDCs. Rather, IL-12 expression by mregDCs is upregulated by interferon-γ but downregulated by IL-4, which is the predominant cytokine in resistant tumors. The authors show that combination therapy with PD-L1 blockade and anti-IL-4 enhances antitumor immunity in a mouse lung cancer model. These findings suggest that combination therapies that include anti-IL-4 might boost antitumor responses to PD-1 blockade.