Tumor-Resident Dendritic Cells and Macrophages Modulate the Accumulation of TCR-Engineered T Cells in Melanoma

• Published in: Molecular therapy 2018-06, Vol.26 (6), p.1471-1481
• Main Authors: Hotblack, Alastair, Holler, Angelika, Piapi, Alice, Ward, Sophie, Stauss, Hans J., Bennett, Clare L.
• Format: Article
• Language: English
• Subjects: adoptive cellular therapy; Animals; Antigens; Antigens, Neoplasm - immunology; Antigens, Neoplasm - metabolism; Cancer; CD11c antigen; CD11c Antigen - immunology; CD11c Antigen - metabolism; Cell activation; Clinical trials; Dendritic cells; Dendritic Cells - metabolism; Diphtheria; Diphtheria toxin; engineered T cells; Flow cytometry; Gene therapy; Heparin-binding EGF-like Growth Factor - immunology; Heparin-binding EGF-like Growth Factor - metabolism; Humans; Immunotherapy, Adoptive - methods; Investigations; Lymphocytes; Lymphocytes T; Macrophages; Macrophages - metabolism; Melanoma; Melanoma, Experimental - metabolism; Mice; Mice, Inbred C57BL; Mice, Knockout; myeloid cells; Original; Peptides; Receptors, Antigen, T-Cell - immunology; Receptors, Antigen, T-Cell - metabolism; Solid tumors; T cell receptors; tumor; Tumors
• ISSN: 1525-0016; 1525-0024
• DOI: 10.1016/j.ymthe.2018.03.011

Ongoing clinical trials explore T cell receptor (TCR) gene therapy as a treatment option for cancer, but responses in solid tumors are hampered by the immunosuppressive microenvironment. The production of TCR gene-engineered T cells requires full T cell activation in vitro, and it is currently unknown whether in vivo interactions with conventional dendritic cells (cDCs) regulate the accumulation and function of engineered T cells in tumors. Using the B16 melanoma model and the inducible depletion of CD11c+ cells in CD11c.diphtheria toxin receptor (DTR) mice, we analyzed the interaction between tumor-resident cDCs and engineered T cells expressing the melanoma-specific TRP-2 TCR. We found that depletion of CD11c+ cells triggered the recruitment of cross-presenting cDC1 into the tumor and enhanced the accumulation of TCR-engineered T cells. We show that the recruited tumor cDCs present melanoma tumor antigen, leading to enhanced activation of TCR-engineered T cells. In addition, detailed analysis of the tumor myeloid compartment revealed that the depletion of a population of DT-sensitive macrophages can contribute to the accumulation of tumor-infiltrating T cells. Together, these data suggest that the relative frequency of tumor-resident cDCs and macrophages may impact the therapeutic efficacy of TCR gene therapy in solid tumors. The extent to which tumor-specific engineered T cells are regulated by endogenous immune cells is unclear. Here, Hotblack et al. exploit depletion of CD11c-expressing myeloid cells to demonstrate that dynamic interactions within the tumor microenvironment control the expansion of engineered T cells.