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

被引：23

作者：

Yang, Chen ^{[1
,2
,3
]}

Geng, Haigang ^{[1
,2
]}

Yang, Xupeng ^{[4
,5
]}

Ji, Shuyi ^{[4
,5
,6
,7
]}

Liu, Zhicheng ^{[8
]}

Feng, Hao ^{[1
,2
]}

Li, Qian ^{[9
]}

Zhang, Tangansu ^{[10
]}

Zhang, Sisi ^{[1
,2
]}

Ma, Xuhui ^{[1
,2
]}

Zhu, Chuchen ^{[1
,2
]}

Xu, Nuo ^{[1
,2
]}

Xia, Yuhan ^{[11
]}

Li, Yan ^{[12
]}

Wang, Hongye ^{[1
,2
]}

Yu, Chune ^{[1
,2
]}

Du, Shangce ^{[3
]}

Miao, Beiping ^{[3
]}

Xu, Lei ^{[8
]}

Wang, Hui ^{[1
,2
]}

Cao, Ying ^{[1
,2
]}

Li, Botai ^{[13
]}

Zhu, Lili ^{[1
,2
]}

Tang, Xiangyu ^{[1
,2
]}

Zhang, Haoyu ^{[1
,2
]}

Zhu, Chunchao ^{[14
]}

Huang, Zhao ^{[8
]}

Leng, Chao ^{[8
]}

Hu, Haiyan ^{[9
]}

Chen, Xiaoping ^{[8
]}

Yuan, Shengxian ^{[15
]}

Jin, Guangzhi ^{[16
]}

Bernards, Rene ^{[17
]}

Sun, Chong ^{[3
]}

Zheng, Quan ^{[18
,19
]}

Qin, Wenxin ^{[1
,2
]}

Gao, Qiang ^{[4
,5
]}

Wang, Cun ^{[1
,2
]}

机构：

[1] Shanghai Jiao Tong Univ, Shanghai Canc Inst, Sch Med, State Key Lab Syst Med Canc, Shanghai, Peoples R China

[2] Shanghai Jiao Tong Univ, Renji Hosp, Sch Med, Dept Liver Surg, Shanghai, Peoples R China

[3] German Canc Res Ctr, DKFZ Charite Cooperat, Heidelberg, Germany

[4] Fudan Univ, Dept Liver Surg & Transplantat, Shanghai, Peoples R China

[5] Fudan Univ, Zhongshan Hosp, Liver Canc Inst, Inst Biomed Sci,State Key Lab Genet Engn,Human Phe, Shanghai, Peoples R China

[6] Tongji Univ, Shanghai East Hosp, Inst Regenerat Med, Med Innovat Ctr,Sch Med, Shanghai, Peoples R China

[7] Tongji Univ, Shanghai East Hosp, Sch Med, State Key Lab Cardiol, Shanghai, Peoples R China

[8] Huazhong Univ Sci & Technol, Tongji Hosp, Tongji Med Coll, Hepat Surg Ctr, Wuhan, Peoples R China

[9] Shanghai Jiao Tong Univ, Shanghai Peoples Hosp 6, Dept Oncol, Sch Med, Shanghai, Peoples R China

[10] Huazhong Univ Sci & Technol, Union Hosp, Tongji Med Coll, Dept Obstet & Gynecol, Wuhan, Peoples R China

[11] Shanghai Jiao Tong Univ, Sch Med, Sch Med, Dept Biliary Pancreat Surg, Shanghai, Peoples R China

[12] Sun Yat Sen Univ, Zhongshan Sch Med, Dept Immunol & Microbiol, Guangzhou, Peoples R China

[13] Shanghai Jiao Tong Univ, Renji Hosp, Shanghai Immune Therapy Inst, Sch Med, Shanghai, Peoples R China

[14] Shanghai Jiao Tong Univ, Renji Hosp, Sch Med, Dept Gastrointestinal Surg, Shanghai, Peoples R China

[15] Eastern Hepatobiliary Surg Hosp, Dept Hepat Surg 3, Shanghai, Peoples R China

[16] Shanghai Jiao Tong Univ, Tongren Hosp, Sch Med, Dept Intervent Radiol, Shanghai, Peoples R China

[17] Netherlands Canc Inst, Oncode Inst, Div Mol Carcinogenesis, Amsterdam, Netherlands

[18] Shanghai Jiao Tong Univ, Ctr Single Cell Om, Sch Publ Hlth, Sch Med, Shanghai, Peoples R China

[19] Peking Univ, Canc Hosp & Inst, Dept Gastrointestinal Canc Translat Res, Key Lab Carcinogenesis & Translat Res,Minist Educ, Beijing, Peoples R China

来源：

CANCER CELL | 2024年 / 42卷 / 12期

基金：

中国国家自然科学基金;

关键词：

HEPATOCELLULAR-CARCINOMA CELLS; STEM-CELLS;

D O I：

10.1016/j.ccell.2024.10.008

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

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.

引用

页码：2064 / 2081.e19

页数：38

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