Cuproptosis in microsatellite stable colon cancer cells affects the cytotoxicity of CD8+T through the WNT signaling pathway

被引:3
作者
Zeng, Jintao [1 ,2 ,3 ]
Chen, Hong [4 ]
Liu, Xing [1 ]
Xia, Haoyun [4 ]
Chen, Liqi [4 ]
Lin, Dajia [4 ]
Wang, Naisen [4 ]
Weng, Chong [4 ]
Guan, Guoxian [1 ,2 ,3 ]
Zheng, Yu [4 ]
机构
[1] Fujian Med Univ, Affiliated Hosp 1, Dept Colorectal Surg, 20 Chazhong Rd,999 Huashan Rd,Zhanggang St, Fuzhou 350001, Peoples R China
[2] Fujian Med Univ, Affiliated Hosp 1, Natl Reg Med Ctr, Dept Colorectal Surg, Binhai Campus, Fuzhou, Peoples R China
[3] Fujian Med Univ, Affiliated Hosp 1, Fujian Abdominal Surg Res Inst, 20 Chazhong Rd,999 Huashan Rd,Zhanggang St, Fuzhou 350001, Peoples R China
[4] Fujian Prov Hosp, Dept Gastrointestinal Surg, Fuzhou 350001, Peoples R China
关键词
Microsatellite stable colon cancer; Cuproptosis; CD8+T cells; WNT signaling; Immunotherapy; R PACKAGE; ANGIOGENESIS; EXPRESSION; COPPER;
D O I
10.1016/j.cbi.2024.111239
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
The microsatellite stable (MSS) colon cancer (CC) has long been considered resistant to immunotherapy. Cuproptosis, as a novel form of cell death, may interact with tumor immunity. This project focused on the impact of cuproptosis on the cytotoxicity of CD8(+)T in MSS CC, aiming to provide effective clues for improving the treatment strategy of MSS CC. The study developed an MSS CC cuproptosis model using 50 nM elesclomol and 1 mu M CuCl2. Cuproptotic SW480 cells were directly co-cultured with CD8(+) T cells. Cuproptosis levels were assessed via intracellular copper ion detection, Western blot, and confocal laser scanning microscopy. CCK-8, Hochest/PI staining, CFSE cell proliferation assay, LDH cytotoxicity detection, and ELISA were used to evaluate CD8(+) T cell immune activity and cytotoxicity. Transcriptome sequencing and bioinformatics analysis identified regulated signals in cuproptotic SW480 cells. A rescue experiment utilized a WNT pathway activator (BML-284). PD-L1 expression in cells/membranes was analyzed using qRT-PCR, Western blot, and flow cytometry. NSG mice were immunoreconstituted, and the effects of cuproptosis on immune infiltration and cancer progression in MSS CC mice were assessed using ELISA and immunohistochemistry (IHC). Treatment with 50 nM elesclomol and 1 mu M CuCl2 significantly increased cuproptosis in SW480 cells. Co-culture with CD8(+) T cells enhanced their cytotoxicity. Sequencing revealed cuproptosis-mediated modulation of immune and inflammatory pathways, including WNT signaling. Rescue experiments showed downregulation of WNT signaling in cuproptotic SW480 cells. Indirectly, CD8(+) T cell immune function was enhanced by reducing PD-L1 expression. In mice, cuproptosis resulted in increased infiltration of CD8(+) T cells in tumor tissue, leading to delayed cancer progression compared to the control group. Cuproptosis in MSS CC cells enhances the cytotoxicity of CD8(+) T cells, which may be achieved through downregulation of the WNT signaling pathway and decreased expression of PD-L1. In the future, drugs that can induce cuproptosis may be a promising approach to improve MSS CC immunotherapy.
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页数:10
相关论文
共 49 条
[1]   Newly identified disorder of copper metabolism caused by variants in CTR1, a high-affinity copper transporter [J].
Batzios, Spyros ;
Tal, Galit ;
DiStasio, Andrew T. ;
Peng, Yanyan ;
Charalambous, Christiana ;
Nicolaides, Paola ;
Kamsteeg, Erik-Jan ;
Korman, Stanley H. ;
Mandel, Hanna ;
Steinbach, Peter J. ;
Yi, Ling ;
Fair, Summer R. ;
Hester, Mark E. ;
Drousiotou, Anthi ;
Kaler, Stephen G. .
HUMAN MOLECULAR GENETICS, 2022, 31 (24) :4121-4130
[2]   Recent advances in Lynch syndrome [J].
Biller, Leah H. ;
Syngal, Sapna ;
Yurgelun, Matthew B. .
FAMILIAL CANCER, 2019, 18 (02) :211-219
[3]  
Carlino MS, 2021, LANCET, V398, P1002, DOI 10.1016/S0140-6736(21)01206-X
[4]   WNT signaling modulates PD-L1 expression in the stem cell compartment of triple-negative breast cancer [J].
Castagnoli, Lorenzo ;
Cancila, Valeria ;
Cordoba-Romero, Sandra L. ;
Faraci, Simona ;
Talarico, Giovanna ;
Belmonte, Beatrice ;
Iorio, Marilena V. ;
Milani, Matteo ;
Volpari, Tatiana ;
Chiodoni, Claudia ;
Hidalgo-Miranda, Alfredo ;
Tagliabue, Elda ;
Tripodo, Claudio ;
Sangaletti, Sabina ;
Di Nicola, Massimo ;
Pupa, Serenella M. .
ONCOGENE, 2019, 38 (21) :4047-4060
[5]   A Cuproptosis Activation Scoring model predicts neoplasm-immunity interactions and personalized treatments in glioma [J].
Chen, Bo ;
Zhou, Xiaoxi ;
Yang, Liting ;
Zhou, Hongshu ;
Meng, Ming ;
Zhang, Liyang ;
Li, Jian .
COMPUTERS IN BIOLOGY AND MEDICINE, 2022, 148
[6]   Copper homeostasis and cuproptosis in health and disease [J].
Chen, Liyun ;
Min, Junxia ;
Wang, Fudi .
SIGNAL TRANSDUCTION AND TARGETED THERAPY, 2022, 7 (01)
[7]   The innate immune effector ISG12a promotes cancer immunity by suppressing the canonical Wnt/β-catenin signaling pathway [J].
Deng, Rilin ;
Zuo, Chaohui ;
Li, Yongqi ;
Xue, Binbin ;
Xun, Zhen ;
Guo, Yanxia ;
Wang, Xiaohong ;
Xu, Yan ;
Tian, Renyun ;
Chen, Shengwen ;
Liu, Qian ;
Chen, Jinwen ;
Wang, Jingjing ;
Huang, Xiang ;
Li, Huiyi ;
Guo, Mengmeng ;
Wang, Xintao ;
Yang, Miaomiao ;
Wu, Zhihui ;
Wang, Jinfeng ;
Ma, Jiahuan ;
Hu, Jun ;
Li, Guangdi ;
Tang, Songqing ;
Tu, Zhengkun ;
Ji, Hongbin ;
Zhu, Haizhen .
CELLULAR & MOLECULAR IMMUNOLOGY, 2020, 17 (11) :1163-1179
[8]   β-Catenin induces transcriptional expression of PD-L1 to promote glioblastoma immune evasion [J].
Du, Linyong ;
Lee, Jong-Ho ;
Jiang, Hongfei ;
Wang, Chengde ;
Wang, Silu ;
Zheng, Zhihong ;
Shao, Fei ;
Xu, Daqian ;
Xia, Yan ;
Li, Jing ;
Zheng, Yanhua ;
Qian, Xu ;
Li, Xinjian ;
Kim, Hyung-Ryong ;
Xing, Dongming ;
Liu, Pengyuan ;
Lu, Zhimin ;
Lyu, Jianxin .
JOURNAL OF EXPERIMENTAL MEDICINE, 2020, 217 (11)
[9]   WNT Signaling in Cancer Immunosurveillance [J].
Galluzzi, Lorenzo ;
Spranger, Stefani ;
Fuchs, Elaine ;
Lopez-Soto, Alejandro .
TRENDS IN CELL BIOLOGY, 2019, 29 (01) :44-65
[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