Tumor-derived retinoic acid promotes monocyte differentiation into immunosuppressive macrophages.

  • Major Finding: Tumor-derived retinoic acid promotes monocyte differentiation into immunosuppressive macrophages.

  • Concept: Blocking retinoic acid signaling reduced sarcoma volume and synergized with anti–PD-1 in mice.

  • Impact: This work flags retinoic acid as a contributor to the immunosuppressive sarcoma microenvironment.

An immunosuppressive tumor microenvironment (TME) characterized by higher numbers of immunosuppressive tumor-associated macrophages (TAM) and lower numbers of immunostimulatory dendritic cells diminishes the efficacy of immunotherapies. For unclear reasons, tumor-infiltrating monocytes appear to preferentially differentiate into TAMs rather than dendritic cells. In experiments using three mouse sarcoma models, Devalaraja and colleagues found evidence that TME-associated factors are responsible for promoting the preferential differentiation of monocytes into TAMs rather than dendritic cells. Further investigation revealed that IL13 derived from T cells in the TME stimulated the production of large amounts of retinoic acid by tumor cells. Retinoic acid signaling appeared to block differentiation of monocytes into TAMs, instead promoting their differentiation into dendritic cells, by regulating the expression of genes encoding transcription factors, including the gene encoding IRF4—a key transcription factor involved in monocyte differentiation into dendritic cells. Reducing production of retinoic acid by tumor cells led to an increase in antigen-presenting cells (APC) and improved the antitumor effects of T cells. Additionally, anti–PD-1 treatment and a reduction in retinoic acid levels exerted a synergistic effect on reduction in sarcoma volume in mice. Similarly, inhibition of intratumoral retinoic acid receptor signaling synergized with immune-checkpoint blockade, promoted the differentiation of tumor-infiltrating monocytes into APCs, and improved the T-cell antitumor response. Finally, analysis of data from The Cancer Genome Atlas suggested that retinoic acid may also contribute to an immunosuppressive TME in human cancers. In summary, this paper provides an explanation for the preferential differentiation of tumor-infiltrating monocytes into immunosuppressive TAMs rather than immunostimulatory dendritic cells and identifies retinoic acid as an important tumor cell–supplied factor modulating the TME. Further, these findings suggest that deeper investigation of the role of retinoic acid in cancer, particularly where it may intersect with immunotherapy response, is warranted.

Devalaraja S, To TKJ, Folkert IW, Natesan R, Alam MZ, Li M, et al. Tumor-derived retinoic acid regulates intratumoral monocyte differentiation to promote immune suppression. Cell 2020 Mar 12 [Epub ahead of print].

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