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

Abstract

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.

Regulatory T Cells Restrain Interleukin-2- and Blimp-1-Dependent Acquisition of Cytotoxic Function by CD4+ T Cells

“…The transduction procedure was performed according to ( Hotblack et al., 2018 ). Briefly, the TRP1 TCR ( Kerkar et al., 2011 , Muranski et al., 2008 ) was cloned into the retroviral vector pMP71 with a 2A sequence separating the Vα3.2 and Vβ14 chains, followed by an internal ribosome entry site (IRES) truncated CD19 sequence.…”

T cell receptor therapy against melanoma—Immunotherapy for the future?

“…Both TRP‐1 and TRP‐2 are associated with breakdown of immune tolerance to melanocytes and the induction of cellular and humoral immunity 55 . TCR targeted against TRP‐1 has shown potential in a murine melanoma model 56,57 …”

Cell Adhesion Molecules and Their Roles and Regulation in the Immune and Tumor Microenvironment

“…DCs orchestrate immune responses and it is now widely appreciated that DCs also play a crucial role in regulating the host immune responses to cancer. Indeed, DCs have been found in various types of tumors both in humans and mice (2, 135–140). In the tumor microenvironment, many tumor cells die naturally or as a result of anti-cancer therapies such as chemotherapy and thus DCs often interact with dying tumor cells enabling them to acquire tumor antigens (141).…”