STAT3 Inhibits CD103+ cDC1 Vaccine Efficacy in Murine Breast Cancer
STAT3 Inhibits CD103+ cDC1 Vaccine Efficacy in Murine Breast Cancer
复制标题
DOI：
10.3390/cancers12010128
复制
发表时间：
2020-01-01
期刊：
影响因子：
5.2
通讯作者：
Watowich, Stephanie S.
中科院分区：
文献类型：
--
作者：
Chrisikos, Taylor T.;Zhou, Yifan;Watowich, Stephanie S.
传统的树突状细胞（cDC）是一个重要的免疫群体，由多个亚群组成，负责控制适应性免疫和耐受。尽管迁移性1型cDC（小鼠中的CD 103（+）cDC 1）对于建立CD 8（+）T细胞介导的抗肿瘤免疫是必需的，但肿瘤是否以及如何调节CD 103（+）cDC 1功能仍有待研究。信号转导和转录激活因子3（STAT 3）介导肿瘤相关免疫抑制细胞因子（如白细胞介素（IL）-10）的细胞内信号传导;因此，我们假设STAT 3抑制CD 103（+）cDC 1诱导的抗肿瘤免疫应答。在此，我们发现体外来源的STAT 3缺陷型（Stat 3（/））CD 103（+）cDC 1对IL-10对Toll样受体3（TLR 3）激动剂诱导的成熟反应的抑制作用是不敏感的。在肿瘤疫苗接种方法中，我们发现Stat 3（/）CD 103（+）cDC 1抑制乳腺肿瘤生长，并比STAT 3-充足的CD 103（+）cDC 1更有效地增加小鼠存活率。此外，与磷酸盐缓冲盐水（PBS）处理的动物相比，Stat 3（/）CD 103（+）cDC 1疫苗接种引起肿瘤和肿瘤引流淋巴结中肿瘤抗原特异性CD 8（+）T细胞和IFN-γ（+）CD 4（+）T细胞数量增加。此外，IL-10受体缺陷型CD 103（+）cDC 1 s控制肿瘤生长的程度与Stat 3（/）CD 103（+）cDC 1 s相似。综上所述，我们的数据揭示了STAT 3在CD 103（+）cDC 1成熟和抗肿瘤免疫调节中的抑制作用。我们的研究结果还表明，IL-10是乳腺癌中CD 103（+）cDC 1中引发免疫抑制性STAT 3信号传导的关键因素。因此，抑制cDC 1中的STAT 3可能提供一种重要的策略，以提高其在肿瘤疫苗接种方法和cDC 1介导的抗肿瘤免疫控制中的功效。
Conventional dendritic cells (cDCs) are a critical immune population, composed of multiple subsets, and responsible for controlling adaptive immunity and tolerance. Although migratory type 1 cDCs (CD103(+) cDC1s in mice) are necessary to mount CD8(+) T cell-mediated anti-tumor immunity, whether and how tumors modulate CD103(+) cDC1 function remain understudied. Signal Transducer and Activator of Transcription 3 (STAT3) mediates the intracellular signaling of tumor-associated immunosuppressive cytokines, such as interleukin (IL)-10; thus, we hypothesized that STAT3 restrained anti-tumor immune responses elicited by CD103(+) cDC1s. Herein, we show that in vitro-derived STAT3-deficient (Stat3(/)) CD103(+) cDC1s are refractory to the inhibitory effects of IL-10 on Toll-like receptor 3 (TLR3) agonist-induced maturation responses. In a tumor vaccination approach, we found Stat3(/) CD103(+) cDC1s restrained mammary gland tumor growth and increased mouse survival more effectively than STAT3-sufficient CD103(+) cDC1s. In addition, vaccination with Stat3(/) CD103(+) cDC1s elicited increased amounts of tumor antigen-specific CD8(+) T cells and IFN-gamma(+) CD4(+) T cells in tumors and tumor-draining lymph nodes versus phosphate-buffered saline (PBS)-treated animals. Furthermore, IL-10 receptor-deficient CD103(+) cDC1s controlled tumor growth to a similar degree as Stat3(/) CD103(+) cDC1s. Taken together, our data reveal an inhibitory role for STAT3 in CD103(+) cDC1 maturation and regulation of anti-tumor immunity. Our results also suggest IL-10 is a key factor eliciting immunosuppressive STAT3 signaling in CD103(+) cDC1s in breast cancer. Thus, inhibition of STAT3 in cDC1s may provide an important strategy to improve their efficacy in tumor vaccination approaches and cDC1-mediated control of anti-tumor immunity.