Inhibiting BTK and IDO Enhances Dendritic Cell–Mediated Immune Response

In response to chemotherapy, dying tumor cells release antigens which can be cross-presented by dendritic cells (DC) to initiate an antitumor immune response, but DCs in the tumor microenvironment (TME) often display dysfunctional phenotypes. Differentiation of precursor cells into activated, inflammatory DCs is important for antitumor immunity, although previous research has suggested that this differentiation step may be inhibited in the TME. Given that indoleamine 2,3-dioxygenase (IDO) and Bruton's tyrosine kinase (BTK) have been implicated in playing immunosuppressive roles in DCs and their precursor cells, Sharma and colleagues investigated whether modulation of DC differentiation via IDO and BTK inhibition could affect the immune response in the context of chemotherapy. Classical DCs can arise from dendritic-lineage precursors but are often rare in tumors, whereas monocytic DCs can differentiate from myeloid precursor cells in the TME. In a murine model of melanoma, treatment of tumor-bearing mice using clinically approved small-molecule inhibitors of BTK and IDO prior to chemotherapy resulted in differentiation of inflammatory monocytic Ly6c⁺CD103⁺ DCs and tumor regression. Moreover, dual inhibition of BTK and IDO in combination with chemotherapy not only activated effector CD8⁺ T cells but also reduced the immunosuppressive phenotype of regulatory T cells. Notably, BTK and IDO inhibition promoted differentiation of inflammatory DCs that arose from monocyte-lineage precursors, rather than from classical dendritic precursors, although chromatin accessibility and single-cell transcriptomic analysis revealed that monocytic Ly6c⁺CD103⁺ DCs and their Ly6c⁺c-kit⁺ precursors were epigenetically and transcriptionally similar to conventional type I DCs and their precursors. Mechanistic studies of monocyte-derived DC-like cells found that, whereas IFNγ stimulation promoted differentiation through mTORC1, TGF-β inhibited differentiation by activating BTK and maintaining expression of IDO, a tryptophan-depleting enzyme, thereby inhibiting mTORC1 via GATOR2-mediated amino acid sensing. In summary, this work describes a BTK–IDO–mTOR axis that controls monocytic differentiation and highlights the potential therapeutic benefit of targeting this axis in combination with chemotherapy to enhance antitumor immunity.

Sharma MD, Pacholczyk R, Shi H, Berrong ZJ, Zakharia Y, Greco A, et al. Inhibition of the BTK-IDO-mTOR axis promotes differentiation of monocyte-lineage dendritic cells and enhances anti-tumor T cell immunity. Immunity 2021;54:2354–71.

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