Activation of the inflammatory transcription factor NF-κB in tumor-associated macrophages (TAMs) is assumed to contribute to tumor promotion. However, whether and how NF-κB drives the antitumor macrophages to become pro-tumorigenic have not been determined in any cancer type yet. Similarly, how TAMs repress CD8+ cytotoxic T lymphocytes (CTLs) remains largely unknown, although their importance in regulatory T (Treg) cell regulation and tumor promotion has been well appreciated. Here, using an endogenous lung cancer model we uncover a direct crosstalk between TAMs and CTLs. TAMs suppress CTLs through the T-cell inhibitory molecule B7x (B7-H4/B7S1) in a cell-cell contact manner, whereas CTLs kill TAMs in a tumor antigen-specific manner. Remarkably, TAMs secrete the known T-cell suppressive cytokine interleukin-10 (IL-10) to activate, but not to repress, CTLs. Notably, one major role of cell-intrinsic NF-κB RelA is to drive TAMs to suppress CTLs for tumor promotion. It induces B7x expression in TAMs directly, and restricts IL-10 expression indirectly by repressing expression of the NF-κB cofactor Bcl3 and subsequent Bcl3/NF-κB1-mediated transcription of IL-10. It also renders TAMs resistant to CTLs by up-regulating anti-apoptotic genes. These studies help understand how immunity is shaped in lung tumorigenesis, and suggest a RelA-targeted immunotherapy for this deadliest cancer.

中文翻译：

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NF-κBRelA使得与肿瘤相关的巨噬细胞具有抵抗力，并能够直接抑制CD8 + T细胞以促进肿瘤。

肿瘤相关巨噬细胞（TAMs）中炎症转录因子NF-κB的激活被认为有助于肿瘤的发展。然而，尚未在任何癌症类型中确定NF-κB是否以及如何驱动抗肿瘤巨噬细胞变成促肿瘤的。类似地，尽管TAMs在调节性T（Treg）细胞调节和肿瘤促进中的重要性已广为人知，但如何抑制CD8 +细胞毒性T淋巴细胞（CTLs）仍然很大程度上未知。在这里，使用内源性肺癌模型，我们发现了TAM和CTL之间的直接串扰。TAM通过T细胞抑制分子B7x（B7-H4 / B7S1）以细胞-细胞接触的方式抑制CTL，而CTL以肿瘤抗原特异性的方式杀死TAM。值得注意的是，TAM会分泌已知的T细胞抑制性细胞因子白介素10（IL-10）来激活，但不要压抑CTL。值得注意的是，细胞内源性NF-κBRelA的主要作用之一是驱动TAM抑制CTL，从而促进肿瘤的发展。它直接诱导TAM中B7x的表达，并通过抑制NF-κB辅因子Bcl3的表达和随后的Bcl3 /NF-κB1介导的IL-10转录而间接限制IL-10的表达。它还通过上调抗凋亡基因使TAM对CTL具有抗性。这些研究有助于了解肺肿瘤发生过程中免疫力的形成方式，并建议针对这种最致命的癌症进行针对Rela的免疫疗法。并通过抑制NF-κB辅因子Bcl3的表达和随后的Bcl3 /NF-κB1介导的IL-10转录而间接限制IL-10的表达。它还通过上调抗凋亡基因使TAM对CTL具有抗性。这些研究有助于了解肺肿瘤发生过程中免疫力的形成方式，并建议针对这种最致命的癌症进行针对Rela的免疫疗法。并通过抑制NF-κB辅因子Bcl3的表达和随后的Bcl3 /NF-κB1介导的IL-10转录而间接限制IL-10的表达。它还通过上调抗凋亡基因使TAM对CTL具有抗性。这些研究有助于了解肺肿瘤发生过程中免疫力的形成方式，并建议针对这种最致命的癌症进行针对Rela的免疫疗法。