Complement is a critical component of humoral immunity implicated in cancer development; however, its biological contributions to tumorigenesis remain poorly understood. Using the K14-HPV16 transgenic mouse model of squamous carcinogenesis, we report that urokinase (uPA)⁺ macrophages regulate C3-independent release of C5a during premalignant progression, which in turn regulates protumorigenic properties of C5aR1⁺ mast cells and macrophages, including suppression of CD8⁺ T cell cytotoxicity. Therapeutic inhibition of C5aR1 via the peptide antagonist PMX-53 improved efficacy of paclitaxel chemotherapy associated with increased presence and cytotoxic properties of CXCR3⁺ effector memory CD8⁺ T cells in carcinomas, dependent on both macrophage transcriptional programming and IFNγ. Together, these data identify C5aR1-dependent signaling as an important immunomodulatory program in neoplastic tissue tractable for combinatorial cancer immunotherapy.

中文翻译：

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补体C5a促进鳞状癌发生，并限制了T细胞对化学疗法的反应。

补体是与癌症发展有关的体液免疫的重要组成部分。然而，其对肿瘤发生的生物学贡献仍然知之甚少。我们使用鳞癌的K14-HPV16转基因小鼠模型，我们报道了尿激酶（uPA）⁺巨噬细胞在恶变前的过程中调节C5独立于C3的释放，进而调节C5aR1 ⁺肥大细胞和巨噬细胞的致瘤特性，包括抑制CD8。⁺ T细胞的细胞毒性。通过肽拮抗剂PMX-53对C5aR1的治疗抑制作用提高了紫杉醇化疗的疗效，并与CXCR3 ⁺效应记忆CD8 ^+的存在和细胞毒性增加有关癌症中的T细胞依赖于巨噬细胞转录程序和IFNγ。总之，这些数据将C5aR1依赖性信号转导为可治疗组合癌免疫治疗的肿瘤组织中的重要免疫调节程序。