期刊名稱：Cancer Cell
影響因子：44.5
文章題目：Targeting the immune privilege of tumor-initiating cells to enhance cancer immunotherapy
DOI：10.1016/j.ccell.2024.10.008
第一作者：Chen Yang
作者單位：上海交通大學(xué)醫(yī)學(xué)院附屬仁濟(jì)醫(yī)院
引用YOBIBIO產(chǎn)品：U96-3145E Mouse Cxcl7/nap-2 ELISA Kit
文獻(xiàn)摘要：
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.
腫瘤起始細(xì)胞 （TIC） 具有逃避抗腫瘤免疫的能力，這可能解釋了癌癥免疫治療的許多失敗。在這里，我們將 CD49f 確定為肝細(xì)胞癌 （HCC） 中識(shí)別 TICs 的重要標(biāo)志物，優(yōu)于其他常用的 TIC 標(biāo)志物。CD49f 高 TICs 通過 CXCL2-CXCR2 軸特異性募集促進(jìn)腫瘤的中性粒細(xì)胞，并在腫瘤微環(huán)境 （TME） 中產(chǎn)生免疫抑制環(huán)境。反相地，中性粒細(xì)胞通過分泌 CCL4 將附近的腫瘤細(xì)胞重編程為 TIC 表型。這些細(xì)胞可以通過 CCL4/STAT3 誘導(dǎo)和 CD49f 穩(wěn)定的 CD155 表達(dá)來逃避 CD8+ T 細(xì)胞介導(dǎo)的殺傷。值得注意的是，雖然異常的 CD155 表達(dá)有助于免疫抑制，但它也代表了 TIC 特異性的脆弱性。我們證明，在臨床前 HCC 模型中，CD155 缺失或抗體阻斷顯著提高了對抗 PD-1 治療的敏感性。我們的研究結(jié)果揭示了腫瘤免疫逃逸的新機(jī)制，并為 CD155 阻斷與抗 PD-1/PD-L1 治療相結(jié)合治療 HCC 提供了理論依據(jù)。
