BATF3 Dendritic Cells Drive Adoptive Effector T-Cell Trafficking

Patient response to immunotherapies such as adoptive T-cell transfer and immune checkpoint blockade, which are effective in a substantial number of patients but fail in a significant subset of patients, is dependent upon the presence of a T cell–inflamed tumor microenvironment (TME). Recent evidence suggests that recruitment of CD8⁺ T cells to the TME is dependent on the chemokines CXCL9/10, which are CXCR3 ligands that are upregulated in response to IFNs. Having recently shown that activation of tumor-intrinsic WNT/CTNNB signaling resulted in the lack of baseline T-cell priming against tumor-associated antigens and decreased recruitment of CD103⁺ dendritic cells (DC) to drive resistance to immune checkpoint therapy, Spranger and colleagues evaluated the efficacy of an exogenous effector T-cell response against autochthonous mouse models of melanoma. Growth of T cell–inflamed murine melanoma tumors, but not non-T cell–inflamed Ctnnb1⁺ mouse melanoma tumors, was controlled by adoptive T-cell transfer or endogenous memory CD8⁺ T cells induced by vaccination. Effector T cells exhibited greater mobility and interaction with tumor cells in T cell–inflamed tumors, which were found to be immunoedited, but not in Ctnnb1⁺ tumors. Evaluation of chemokine receptor expression revealed that CD3⁺ T cells in non-T cell–inflamed tumors expressed CXCR3-expressing CD3⁺ T cells, whereas T cells in Ctnnb1⁺ tumors did not express CXCR3 or CCR5. Similarly, CD103⁺ DCs, which were increased in non-T cell–inflamed tumors compared to Ctnnb1⁺ tumors, produced CXCL9/10 in non-T cell–inflamed tumors but not in Ctnnb1⁺ tumors, and the production of CXCL10 by BATF3-lineage CD103⁺ DCs was found to be crucial for effector T-cell recruitment to the TME. These findings provide evidence that tumor-resident CD103⁺ DCs are critical for the establishment of the T cell–inflamed TME and suggest a potential therapeutic strategy to overcome clinical resistance to immunotherapies.

Spranger S, Dai D, Horton B, Gajewski TF. Tumor-residing Batf3 dendritic cells are required for effector T cell trafficking and adoptive T cell therapy. Cancer Cell 2017;31:711–23.

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