PDF(Pubmed)
Abstract：
Cancer cells can evade immune elimination by activating immunosuppressive signaling pathways in the tumor microenvironment (TME). Targeting immunosuppressive signaling pathways to promote antitumor immunity has become an attractive strategy for cancer therapy. Aurora-A is a well-known oncoprotein that plays a critical role in tumor progression, and its inhibition is considered a promising strategy for treating cancers. However, targeting Aurora-A has not yet got a breakthrough in clinical trials. Recent reports have indicated that inhibition of oncoproteins may reduce antitumor immunity, but the role of tumor-intrinsic Aurora-A in regulating antitumor immunity remains unclear. In this study, we demonstrated that in tumors with high lymphocyte infiltration (hot tumors), higher tumor-intrinsic Aurora-A expression is associated with a better prognosis in CRC patients. Mechanically, tumor-intrinsic Aurora-A promotes the cytotoxic activity of CD8+ T cells in immune hot CRC via negatively regulating interleukin-16 (IL-16), and the upregulation of IL-16 may impair the therapeutic effect of Aurora-A inhibition. Consequently, combination treatment with IL-16 neutralization improves the therapeutic response to Aurora-A inhibitors in immune hot CRC tumors. Our study provides evidence that tumor-intrinsic Aurora-A contributes to anti-tumor immunity depending on the status of lymphocyte infiltration, highlighting the importance of considering this aspect in cancer therapy targeting Aurora-A. Importantly, our results suggest that combining Aurora-A inhibitors with IL-16-neutralizing antibodies may represent a novel and effective approach for cancer therapy, particularly in tumors with high levels of lymphocyte infiltration.
摘要：
癌细胞可以通过激活肿瘤微环境（TME）中的免疫抑制信号通路来逃避免疫消除。靶向免疫抑制信号通路以促进抗肿瘤免疫已成为癌症治疗的有吸引力的策略。Aurora-A是一种众所周知的癌蛋白，在肿瘤进展中起着关键作用，它的抑制作用被认为是治疗癌症的一种有前途的策略。然而,针对Aurora-A的临床试验尚未取得突破。最近的报道表明，抑制癌蛋白可能会降低抗肿瘤免疫力，但肿瘤固有Aurora-A在调节抗肿瘤免疫中的作用尚不清楚.在这项研究中,我们证明了在高淋巴细胞浸润的肿瘤（热肿瘤）中，在CRC患者中,较高的肿瘤固有Aurora-A表达与较好的预后相关.机械上,肿瘤固有Aurora-A通过负调节白介素-16（IL-16）促进免疫热结直肠癌中CD8+T细胞的细胞毒性活性，IL-16的上调可能会损害Aurora-A抑制的治疗效果。因此,IL-16中和联合治疗可改善免疫热CRC肿瘤中Aurora-A抑制剂的治疗反应.我们的研究提供了证据，表明肿瘤固有的Aurora-A有助于抗肿瘤免疫，这取决于淋巴细胞浸润的状态，强调在针对Aurora-A的癌症治疗中考虑这方面的重要性。重要的是,我们的研究结果表明，Aurora-A抑制剂与IL-16中和抗体的组合可能是一种新的和有效的癌症治疗方法，特别是在有高水平淋巴细胞浸润的肿瘤中。
