细胞毒T淋巴细胞相关抗原4 (CTLA4) 的抗体可通过激活 T细胞来抑制肿瘤生长，已取得了较好的临床疗效。但多数癌症病人仍耐受该疗法，其作用机理也不很清楚。我们预实验研究发现：CTLA4抗体治疗增加了肿瘤浸润的嗜酸性粒细胞和诱导了肿瘤血管的形态正常化。这些变化只发生在对其敏感的乳腺癌中。最近的报道表明嗜酸性粒细胞能调控肿瘤血管。据此，我们提出科学假说：嗜酸性粒细胞通过诱导肿瘤血管正常化来介导CTLA4抗体对乳腺癌的抑制作用。为了验证这个假说，本项目将阐明CTLA4抗体对嗜酸性粒细胞功能的影响及机制；研究CTLA4抗体可否诱导肿瘤血管正常化及其机理；和分析嗜酸性粒细胞变化、肿瘤血管正常化与CTLA4抗体疗效之间的相关性。本项目的顺利完成将阐明CTLA4抗体治疗的新机理和揭示乳腺癌对CTLA4抗体治疗的耐受机制。这些工作将为临床上克服CTLA4抗体治疗的耐受和推动乳腺癌免疫治疗奠定理论基础。

Ipilimumab, an anti-cytotoxic T lymphocyte-associated antigen-4 (CTLA4) monoclonal antibody, shows impressive efficacy in the clinic, but most of cancer patients remain resistance to anti-CTLA4 therapy. Activation of T cells has been considered as a major mechanism of CTLA4 blockade, but it can’t fully explain the mechanisms of the efficacy or the resistance of anti-CTLA4 therapy. Our preliminary study found that CTLA4 blockade increased tumor-infiltrating eosinophils (EOS) and induced the morphological normalization of tumor vessels in the sensitive breast cancers, compared to the resistant ones. Recent study also suggested that EOS is able to regulate tumor vessel function. Thus, we hypothesized that EOS mediates the regression of breast cancer induced by anti-CTLA4 therapy via vascular normalization. To test this hypothesis, we will investigate the effect of anti-CTLA4 therapy on the recruitment and function of EOS in breast cancers, determine whether anti-CTLA4 treatment is able to induce vascular normalization through the activation of EOS, and analyze the casual relationship between the efficacy of anti-CTLA4 therapy and the changes of EOS and tumor vessels. The completion of this project will not only uncover a novel mechanism of anti-CTLA4 therapy, but also get insight into the resistant mechanisms of breast cancer to CTLA4 blockade. These findings may lead to develop novel strategies to substantially improve the efficacy of immune checkpoint therapy in clinic.