Qiu Connie C, Kotredes Kevin P, Cremers Tess, Patel Sajan, Afanassiev Alexandra, Slifker Michael, Gallucci Stefania, Gamero Ana M
Laboratory of Dendritic Cell Biology, Department of Microbiology and Immunology, Lewis Katz School of Medicine at Temple University, Philadelphia, PA, USA.
Department of Medical Genetics and Molecular Biochemistry, Lewis Katz School of Medicine at Temple University, Philadelphia, PA, USA.
Oncoimmunology. 2020 Dec 29;10(1):1860477. doi: 10.1080/2162402X.2020.1860477.
STAT2 is a central component of the ISGF3 transcriptional complex downstream of type I interferon (IFN-I) signaling. The significance of IFN-I/STAT1 signals in cDCs is well-established in the generation of antitumor cytotoxic T cell (CTL) responses. However, the role of STAT2 has remained elusive. Here, we report a clinical correlation between cDC markers and STAT2 associated with better survival in human metastatic melanoma. In a murine tumor transplantation model, targeted deletion in CD11c+cDCs enhanced tumor growth unaffected by IFNβ therapy. Furthermore, STAT2 was essential for both, the activation of CD8a+cDCs and CD11b+cDCs and antigen cross-presentation for the generation of robust T cell killing response. In contrast, STAT2 in CD11c+cDCs was dispensable for stimulating an antigen-specific humoral response, which was impaired in global deficient mice. Thus, our studies indicate that STAT2 in cDCs is critical in host IFN-I signals by sculpting CTL responses against tumors.
信号转导和转录激活因子2（STAT2）是I型干扰素（IFN-I）信号下游ISGF3转录复合物的核心组成部分。IFN-I/STAT1信号在树突状细胞（cDC）中对抗肿瘤细胞毒性T细胞（CTL）反应产生中的重要作用已得到充分证实。然而，STAT2的作用仍不明确。在此，我们报告了cDC标志物与STAT2之间的临床相关性，这与人类转移性黑色素瘤患者更好的生存率相关。在小鼠肿瘤移植模型中，CD11c⁺ cDCs中的靶向缺失增强了肿瘤生长，且不受IFNβ治疗的影响。此外，STAT2对于CD8a⁺ cDCs和CD11b⁺ cDCs的激活以及抗原交叉呈递以产生强大的T细胞杀伤反应均至关重要。相比之下，CD11c⁺ cDCs中的STAT2对于刺激抗原特异性体液反应是可有可无的，而在全身缺陷小鼠中该反应受损。因此，我们的研究表明，cDCs中的STAT2通过塑造针对肿瘤的CTL反应，在宿主IFN-I信号中起关键作用。
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