Targeting VCP potentiates immune checkpoint therapy for colorectal cancer

被引：5

作者：

Wang, Fang ^{[1
]}

Qi, Qi ^{[1
,2
]}

Qin, Baif ^{[3
,4
]}

Wang, Yiwei ^{[5
]}

Huang, Youwei ^{[1
,6
,7
]}

Li, Qing ^{[1
]}

Shen, Xi ^{[1
]}

Wang, Xiangyu ^{[1
]}

Yang, Shangqi ^{[1
]}

Pan, Guopeng ^{[1
]}

Chen, Jiahong ^{[1
,8
]}

Qin, Zixi ^{[1
]}

Chen, Xueqin ^{[1
]}

Yang, Yuqing ^{[1
]}

Zeng, Yuequan ^{[1
]}

Liu, Jun ^{[1
]}

Li, Yuqin ^{[1
]}

Li, Ying ^{[1
]}

Cheng, Zexiong ^{[1
]}

Lin, Xi ^{[1
]}

Xing, Fan ^{[9
]}

Zhang, Yubo ^{[1
]}

Wang, Guocai ^{[10
]}

Li, Kai ^{[4
]}

Jiang, Zhenyou ^{[5
,11
]}

Zhang, Haipeng ^{[1
,11
]}

机构：

[1] Jinan Univ, Sch Med, Dept Pharmacol, Guangzhou 510632, Guangdong, Peoples R China

[2] Jinan Univ, MOE Key Lab Tumor Mol Biol, Sch Med, Guangzhou 510632, Guangdong, Peoples R China

[3] Jinan Univ, Inst Mol & Med Virol, Key Lab, Minist Educ Viral Pathogenesis & Infect Prevent &, Guangzhou 510632, Guangdong, Peoples R China

[4] Sun Yat Sen Univ, Guangdong Res Inst Gastroenterol, Affiliated Hosp 6, Guangzhou 510655, Guangdong, Peoples R China

[5] Jinan Univ, Sch Med, Dept Microbiol & Immunol, Guangzhou 510632, Guangdong, Peoples R China

[6] Jinan Univ, Zhuhai Inst Translat Med, Zhuhai Peoples Hosp, Zhuhai 519000, Guangdong, Peoples R China

[7] Jinan Univ, Biomed Translat Res Inst, Hlth Sci Ctr, Sch Med, Guangzhou 510632, Guangdong, Peoples R China

[8] Peking Univ, Inst Cardiovasc Sci, Sch Basic Med Sci, Beijing 100191, Peoples R China

[9] Guangdong Prov Peoples Hosp & Guangdong Acad Med S, Guangzhou 510080, Guangdong, Peoples R China

[10] Jinan Univ, Inst Tradit Chinese Med & Nat Prod, Guangdong Prov Key Lab Pharmacodynam Constituents, Coll Pharm, Guangzhou 510632, Guangdong, Peoples R China

[11] Jinan Univ, Key Lab Viral Pathogenesis & Infect Prevent & Cont, Minist Educ, Guangzhou 510632, Peoples R China

来源：

CELL REPORTS | 2023年 / 42卷 / 11期

基金：

中国国家自然科学基金; 美国国家科学基金会;

关键词：

IMMUNOGENIC CELL-DEATH; VALOSIN-CONTAINING PROTEIN; ELEVATED EXPRESSION; ATPASE P97; AAA-ATPASE; BLOCKADE; CHEMOTHERAPY; PD-L1;

D O I：

10.1016/j.celrep.2023.113318

中图分类号：

Q2 [细胞生物学];

学科分类号：

071009 ; 090102 ;

摘要：

Immune checkpoint blockade therapies are still ineffective for most patients with colorectal cancer (CRC). Immunogenic cell death (ICD) enables the release of key immunostimulatory signals to drive efficient anti -tumor immunity, which could be used to potentiate the effects of immune checkpoint inhibitors. Here, we showed that inhibition of valosin-containing protein (VCP) elicits ICD in CRC. Meanwhile, VCP inhibitor upregulates PD-L1 expression and compromises antitumor immunity in vivo. Mechanistically, VCP transcription-ally regulates PD-L1 expression in a JAK1-dependent manner. Combining VCP inhibitor with anti-PD1 remodels tumor immune microenvironment and reduces tumor growth in mouse models of CRC. Addition of oncolytic virus further augments the therapeutic activity of the combination regimen. Our study shows the molecular mechanism for regulating PD-L1 expression by VCP and suggests that inhibition of VCP has the potential to increase the efficacy of immunotherapy in CRC.

引用

页数：22

共 41 条

[1] Targeting the AAA ATPase p97 as an Approach to Treat Cancer through Disruption of Protein Homeostasis [J].

Anderson, Daniel J. ;

Le Moigne, Ronan ;

Djakovic, Stevan ;

Kumar, Brajesh ;

Rice, Julie ;

Wong, Steve ;

Wang, Jinhai ;

Yao, Bing ;

Valle, Eduardo ;

von Soly, Szerenke Kiss ;

Madriaga, Antonett ;

Soriano, Ferdie ;

Menon, Mary-Kamala ;

Wu, Zhi Yong ;

Kampmann, Martin ;

Chen, Yuwen ;

Weissman, Jonathan S. ;

Aftab, Blake T. ;

Yakes, F. Michael ;

Shawver, Laura ;

Zhou, Han-Jie ;

Wustrow, David ;

Rolfe, Mark .

CANCER CELL, 2015, 28 (05) :653-665

[2] Pembrolizumab in Microsatellite-Instability-High Advanced Colorectal Cancer [J].

Andre, T. ;

Shiu, K-K ;

Kim, T. W. ;

Jensen, B., V ;

Jensen, L. H. ;

Punt, C. ;

Smith, D. ;

Garcia-Carbonero, R. ;

Benavides, M. ;

Gibbs, P. ;

de la Fouchardiere, C. ;

Rivera, F. ;

Elez, E. ;

Bendell, J. ;

Le, D. T. ;

Yoshino, T. ;

Van Cutsem, E. ;

Yang, P. ;

Farooqui, M. Z. H. ;

Marinello, P. ;

Diaz, L. A., Jr. .

NEW ENGLAND JOURNAL OF MEDICINE, 2020, 383 (23) :2207-2218

[3] MYC regulates the antitumor immune response through CD47 and PD-L1 [J].

Casey, Stephanie C. ;

Tong, Ling ;

Li, Yulin ;

Do, Rachel ;

Walz, Susanne ;

Fitzgerald, Kelly N. ;

Gouw, Arvin M. ;

Baylot, Virginie ;

Guetgemann, Ines ;

Eilers, Martin ;

Felsher, Dean W. .

SCIENCE, 2016, 352 (6282) :227-231

[4] Cdk5 disruption attenuates tumor PD-L1 expression via regulation of IFN-γ signaling components and promotes antitumor immunity [J].

Dorand, Rodney D., Jr. ;

Nthale, Joseph ;

Myers, Jay T. ;

Barkauskas, Deborah S. ;

Avril, Stefanie ;

Chirieleison, Steven M. ;

Pareek, Tej K. ;

Abbott, Derek W. ;

Stearns, Duncan S. ;

Letterio, John J. ;

Huang, Alex Y. ;

Petrosiute, Agne .

CANCER IMMUNOLOGY RESEARCH, 2016, 4 (11)

[5] Turning Cold into Hot: Firing up the Tumor Microenvironment [J].

Duan, Qianqian ;

Zhang, Hualing ;

Zheng, Junnian ;

Zhang, Lianjun .

TRENDS IN CANCER, 2020, 6 (07) :605-618

[6] Calreticulin Expression in Human Non-Small Cell Lung Cancers Correlates with Increased Accumulation of Antitumor Immune Cells and Favorable Prognosis [J].

Fucikova, Jitka ;

Becht, Etienne ;

Iribarren, Kristina ;

Goc, Jeremy ;

Remark, Romain ;

Damotte, Diane ;

Alifano, Marco ;

Devi, Priyanka ;

Biton, Jerome ;

Germain, Claire ;

Lupo, Audrey ;

Fridman, Wolf Herve ;

Dieu-Nosjean, Marie-Caroline ;

Kroemer, Guido ;

Sautes-Fridman, Catherine ;

Cremer, Isabelle .

CANCER RESEARCH, 2016, 76 (07) :1746-1756

[7] Immunological Effects of Conventional Chemotherapy and Targeted Anticancer Agents [J].

Galluzzi, Lorenzo ;

Buque, Aitziber ;

Kepp, Oliver ;

Zitvogel, Laurence ;

Kroemer, Guido .

CANCER CELL, 2015, 28 (06) :690-714

[8] Approaches to treat immune hot, altered and cold tumours with combination immunotherapies [J].

Galon, Jerome ;

Bruni, Daniela .

NATURE REVIEWS DRUG DISCOVERY, 2019, 18 (03) :197-218

[9] Optimizing immunotherapy for colorectal cancer [J].

Ganesh, Karuna .

NATURE REVIEWS GASTROENTEROLOGY & HEPATOLOGY, 2022, 19 (02) :93-94

[10] Immunotherapy in colorectal cancer: rationale, challenges and potential [J].

Ganesh, Karuna ;

Stadler, Zsofia K. ;

Cercek, Andrea ;

Mendelsohn, Robin B. ;

Shia, Jinru ;

Segal, Neil H. ;

Diaz, Luis A., Jr. .

NATURE REVIEWS GASTROENTEROLOGY & HEPATOLOGY, 2019, 16 (06) :361-375

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