Institute for Immunity and Transplantation, Division of Infection and Immunity, University College London, London NW3 2PF, UK.
Institute for Immunity and Transplantation, Division of Infection and Immunity, University College London, London NW3 2PF, UK; Cancer Institute, Division of Cancer Studies, University College London, London WC1E 6DD, UK.
Mol Ther. 2018 Jun 6;26(6):1471-1481. doi: 10.1016/j.ymthe.2018.03.011. Epub 2018 Mar 16.
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.
正在进行的临床试验探索 T 细胞受体 (TCR) 基因治疗作为癌症的一种治疗选择，但实体瘤中的反应受到免疫抑制微环境的阻碍。TCR 基因工程 T 细胞的产生需要在体外充分激活 T 细胞，目前尚不清楚体内与常规树突状细胞 (cDC) 的相互作用是否调节工程 T 细胞在肿瘤中的积累和功能。使用 B16 黑色素瘤模型和 CD11c.diphtheria 毒素受体 (DTR) 小鼠中 CD11c 细胞的诱导性耗竭，我们分析了肿瘤驻留 cDC 与表达黑色素瘤特异性 TRP-2 TCR 的工程 T 细胞之间的相互作用。我们发现 CD11c 细胞的耗竭触发了交叉呈递 cDC1 进入肿瘤的募集，并增强了 TCR 工程 T 细胞的积累。我们表明，募集的肿瘤 cDC 呈递黑色素瘤肿瘤抗原，导致 TCR 工程 T 细胞的激活增强。此外，对肿瘤髓样细胞区室的详细分析表明，耗竭一群对 DT 敏感的巨噬细胞可有助于浸润肿瘤的 T 细胞的积累。总之，这些数据表明肿瘤驻留 cDC 和巨噬细胞的相对频率可能会影响 TCR 基因治疗在实体瘤中的治疗效果。
