T细胞癌症治疗需要CD40-CD40L激活肿瘤坏死因子以及诱导产生一氧化氮合酶的树突状细胞。
T Cell Cancer Therapy Requires CD40-CD40L Activation of Tumor Necrosis Factor and Inducible Nitric-Oxide-Synthase-Producing Dendritic Cells.
作者信息
Marigo Ilaria, Zilio Serena, Desantis Giacomo, Mlecnik Bernhard, Agnellini Andrielly H R, Ugel Stefano, Sasso Maria Stella, Qualls Joseph E, Kratochvill Franz, Zanovello Paola, Molon Barbara, Ries Carola H, Runza Valeria, Hoves Sabine, Bilocq Amélie M, Bindea Gabriela, Mazza Emilia M C, Bicciato Silvio, Galon Jérôme, Murray Peter J, Bronte Vincenzo
机构信息
Istituto Oncologico Veneto, IOV-IRCCS, 35128 Padova, Italy.
Oncology and Immunology Section, Department of Surgery, Oncology and Gastroenterology, University of Padova, 35128 Padova, Italy.
出版信息
Cancer Cell. 2016 Sep 12;30(3):377-390. doi: 10.1016/j.ccell.2016.08.004.
Effective cancer immunotherapy requires overcoming immunosuppressive tumor microenvironments. We found that local nitric oxide (NO) production by tumor-infiltrating myeloid cells is important for adoptively transferred CD8(+) cytotoxic T cells to destroy tumors. These myeloid cells are phenotypically similar to inducible nitric oxide synthase (NOS2)- and tumor necrosis factor (TNF)-producing dendritic cells (DC), or Tip-DCs. Depletion of immunosuppressive, colony stimulating factor 1 receptor (CSF-1R)-dependent arginase 1(+) myeloid cells enhanced NO-dependent tumor killing. Tumor elimination via NOS2 required the CD40-CD40L pathway. We also uncovered a strong correlation between survival of colorectal cancer patients and NOS2, CD40, and TNF expression in their tumors. Our results identify a network of pro-tumor factors that can be targeted to boost cancer immunotherapies.
有效的癌症免疫疗法需要克服免疫抑制性肿瘤微环境。我们发现肿瘤浸润性髓样细胞产生的局部一氧化氮（NO）对于过继转移的CD8(+) 细胞毒性T细胞破坏肿瘤很重要。这些髓样细胞在表型上类似于产生诱导型一氧化氮合酶（NOS2）和肿瘤坏死因子（TNF）的树突状细胞（DC），即Tip-DC。免疫抑制性、集落刺激因子1受体（CSF-1R）依赖性精氨酸酶1(+) 髓样细胞的消耗增强了NO依赖性肿瘤杀伤。通过NOS2消除肿瘤需要CD40-CD40L途径。我们还发现结直肠癌患者的生存率与其肿瘤中NOS2、CD40和TNF表达之间存在很强的相关性。我们的结果确定了一个促肿瘤因子网络，可针对该网络来增强癌症免疫疗法。
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