上海交通大学王存等研究人员合作发现，靶向肿瘤启动细胞的免疫豁免来增强癌症免疫疗法。2024年11月7日，国际知名学术期刊《癌细胞》在线发表了这一成果。

研究人员鉴定出CD49f作为区分肝细胞癌（HCC）中肿瘤启动细胞（TIC）的显著标志物，优于其他常用的TIC标志物。CD49f高表达的TIC通过CXCL2-CXCR2轴特异性招募促肿瘤中性粒细胞，并在肿瘤微环境（TME）中创造免疫抑制环境。

反过来，中性粒细胞通过分泌CCL4将附近的肿瘤细胞重编程为TIC表型。这些细胞可以通过CCL4/STAT3诱导和CD49f稳定化的CD155表达逃避CD8⁺ T细胞介导的杀伤。值得注意的是，尽管异常的CD155表达有助于免疫抑制，但它也代表了TIC特有的脆弱点。

研究人员证明，无论是删除CD155还是抗体阻断，都能显著提高预临床HCC模型对抗PD-1治疗的敏感性。该研究揭示了肿瘤免疫逃逸的一个新机制，并为将CD155阻断与抗PD-1/PD-L1疗法联合应用于HCC提供了理论依据。

据了解，TIC具有逃避抗肿瘤免疫的能力，这可能解释了许多癌症免疫疗法的失败。

附：英文原文

Title: Targeting the immune privilege of tumor-initiating cells to enhance cancer immunotherapy

Author: Chen Yang, Haigang Geng, Xupeng Yang, Shuyi Ji, Zhicheng Liu, Hao Feng, Qian Li, Tangansu Zhang, Sisi Zhang, Xuhui Ma, Chuchen Zhu, Nuo Xu, Yuhan Xia, Yan Li, Hongye Wang, Chune Yu, Shangce Du, Beiping Miao, Lei Xu, Hui Wang, Ying Cao, Botai Li, Lili Zhu, Xiangyu Tang, Haoyu Zhang, Chunchao Zhu, Zhao Huang, Chao Leng, Haiyan Hu, Xiaoping Chen, Shengxian Yuan, Guangzhi Jin, René Bernards, Chong Sun, Quan Zheng, Wenxin Qin, Qiang Gao, Cun Wang

Issue&Volume: 2024-11-07

Abstract: Tumor-initiating cells (TICs) possess the ability to evade anti-tumor immunity, potentially explaining many failures of cancer immunotherapy. Here, we identify CD49f as a prominent marker for discerning TICs in hepatocellular carcinoma (HCC), outperforming other commonly used TIC markers. CD49f-high TICs specifically recruit tumor-promoting neutrophils via the CXCL2-CXCR2 axis and create an immunosuppressive milieu in the tumor microenvironment (TME). Reciprocally, the neutrophils reprogram nearby tumor cells toward a TIC phenotype via secreting CCL4. These cells can evade CD8+ T cell-mediated killing through CCL4/STAT3-induced and CD49f-stabilized CD155 expression. Notably, while aberrant CD155 expression contributes to immune suppression, it also represents a TIC-specific vulnerability. We demonstrate that either CD155 deletion or antibody blockade significantly enhances sensitivity to anti-PD-1 therapy in preclinical HCC models. Our findings reveal a new mechanism of tumor immune evasion and provide a rationale for combining CD155 blockade with anti-PD-1/PD-L1 therapy in HCC.

DOI: 10.1016/j.ccell.2024.10.008

Source: https://www.cell.com/cancer-cell/abstract/S1535-6108(24)00396-9