Immunology

Conventional type 1 dendritic cells (DC1) have been shown to mediate responses to immune-checkpoint blockade in pre-clinical models, and their presence is associated with improved survival in patients with cancer. However, in seeming contradic-tion, DC1s are also found in some tumors that are resistant to immune-checkpoint blockade, raising the question of why DC1s do not function as expected in these tumors. In mouse models of lung adenocarcinoma, Maier, Leader, and colleagues used single-cell RNA sequencing (scRNA-seq) to identify and tran-scriptionally define a previously uncharacterized type of DC they dubbed “mature DCs enriched in immunoregulatory molecules” (mregDC) because of their expression of immunoregulatory genes such as Cd274, Pdcd1lg2, and Cd200 along with maturation genes such as Cd40, Ccr7, and Il12b. Further experiments showed that both DC1s and DC2s were capable of differentiating into mregDCs, and induction of the mregDC program in DC1s was associated with tumor-antigen uptake. Additionally, induction of the receptor tyrosine kinase AXL in mregDCs led to upregula-tion of PD-L1, whereas IFNγ was required for IL12 upregulation. IL4 signaling negatively regulated IL12 production in DC1s, andblocking IL4 restored IFNγ-mediated IL12 production while having no effect on PD-L1 expression. Notably, blocking IL4 during mregDC development in vivo increased the immunogenicity of mregDCs, in turn promoting T-cell effector function. Demon-strating the potential relevance of these findings for patients, scRNA-seq of matched human non–small cell lung cancer sam-ples and adjacent healthy tissue revealed a cell population tran-scriptionally reminiscent of mouse mregDCs. Although they were broadly similar to mouse mregDCs, these human mregDCs also highly expressed some T_h2 response genes, such as IL4R, IL4I1, CCL17, CCL22, and BCL2L1. As with mouse mregDCs, human mregDCs appeared to arise from DC1s as well as DC2s. Collectively, these results identify a previously unknown cluster of tumor-infiltrating DCs and reveal that IL4 blockade may rescue their immunogenicity, providing new insights that may be useful for increasing the functionality of this DC population.