1. Cancer Research Center, First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei 230027, China 2. National Center for Liver Cancer, Naval Medical University (Second Military Medical University), Shanghai 201805, China 3. International Co-operation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Hospital, Naval Medical University (Second Military Medical University), Shanghai 200438, China 4. Shanghai Key Laboratory of Hepato-biliary Tumor Biology, Shanghai 200438, China 5. Key Laboratory of Signaling Regulation and Targeting Therapy of Liver Cancer, Ministry of Education, Shanghai 200438, China
Crosstalk between cancer cells and the immune microenvironment is determinant for liver cancer progression. A tumor subpopulation called liver cancer stem cells (CSCs) significantly accounts for the initiation, metastasis, therapeutic resistance, and recurrence of liver cancer. Emerging evidence demonstrates that the interaction between liver CSCs and immune cells plays a crucial role in shaping an immunosuppressive microenvironment and determining immunotherapy responses. This review sheds light on the bidirectional crosstalk between liver CSCs and immune cells for liver cancer progression, as well as the underlying molecular mechanisms after presenting an overview of liver CSCs characteristic and their microenvironment. Finally, we discuss the potential application of liver CSCs-targeted immunotherapy for liver cancer treatment.
H Sung, J Ferlay, RL Siegel, M Laversanne, I Soerjomataram, A Jemal, F Bray. Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin 2021; 71(3): 209–249 https://doi.org/10.3322/caac.21660
2
A Huang, XR Yang, WY Chung, AR Dennison, J Zhou. Targeted therapy for hepatocellular carcinoma. Signal Transduct Target Ther 2020; 5(1): 146 https://doi.org/10.1038/s41392-020-00264-x
3
S Jörs, P Jeliazkova, M Ringelhan, J Thalhammer, S Dürl, J Ferrer, M Sander, M Heikenwalder, RM Schmid, JT Siveke, F Geisler. Lineage fate of ductular reactions in liver injury and carcinogenesis. J Clin Invest 2015; 125(6): 2445–2457 https://doi.org/10.1172/JCI78585
4
JM Llovet, J Bruix. Systematic review of randomized trials for unresectable hepatocellular carcinoma: chemoembolization improves survival. Hepatology 2003; 37(2): 429–442 https://doi.org/10.1053/jhep.2003.50047
5
N Oishi, T Yamashita, S Kaneko. Molecular biology of liver cancer stem cells. Liver Cancer 2014; 3(2): 71–84 https://doi.org/10.1159/000343863
6
I Joo, H Kim, JM Lee. Cancer stem cells in primary liver cancers: pathological concepts and imaging findings. Korean J Radiol 2015; 16(1): 50–68 https://doi.org/10.3348/kjr.2015.16.1.50
G He, D Dhar, H Nakagawa, J Font-Burgada, H Ogata, Y Jiang, S Shalapour, E Seki, SE Yost, K Jepsen, KA Frazer, O Harismendy, M Hatziapostolou, D Iliopoulos, A Suetsugu, RM Hoffman, R Tateishi, K Koike, M Karin. Identification of liver cancer progenitors whose malignant progression depends on autocrine IL-6 signaling. Cell 2013; 155(2): 384–396 https://doi.org/10.1016/j.cell.2013.09.031
11
K Wu, J Ding, C Chen, W Sun, BF Ning, W Wen, L Huang, T Han, W Yang, C Wang, Z Li, MC Wu, GS Feng, WF Xie, HY Wang. Hepatic transforming growth factor beta gives rise to tumor-initiating cells and promotes liver cancer development. Hepatology 2012; 56(6): 2255–2267 https://doi.org/10.1002/hep.26007
12
Y Tang, K Kitisin, W Jogunoori, C Li, CX Deng, SC Mueller, HW Ressom, A Rashid, AR He, JS Mendelson, JM Jessup, K Shetty, M Zasloff, B Mishra, EP Reddy, L Johnson, L Mishra. Progenitor/stem cells give rise to liver cancer due to aberrant TGF-β and IL-6 signaling. Proc Natl Acad Sci USA 2008; 105(7): 2445–2450 https://doi.org/10.1073/pnas.0705395105
13
Y Jing, K Sun, W Liu, D Sheng, S Zhao, L Gao, L Wei. Tumor necrosis factor-α promotes hepatocellular carcinogenesis through the activation of hepatic progenitor cells. Cancer Lett 2018; 434: 22–32 https://doi.org/10.1016/j.canlet.2018.07.001
14
Á Holczbauer, VM Factor, JB Andersen, JU Marquardt, DE Kleiner, C Raggi, M Kitade, D Seo, H Akita, ME Durkin, SS Thorgeirsson. Modeling pathogenesis of primary liver cancer in lineage-specific mouse cell types. Gastroenterology 2013; 145(1): 221–231 https://doi.org/10.1053/j.gastro.2013.03.013
15
X Mu, R Español-Suñer, I Mederacke, S Affò, R Manco, C Sempoux, FP Lemaigre, A Adili, D Yuan, A Weber, K Unger, M Heikenwälder, IA Leclercq, RF Schwabe. Hepatocellular carcinoma originates from hepatocytes and not from the progenitor/biliary compartment. J Clin Invest 2015; 125(10): 3891–3903 https://doi.org/10.1172/JCI77995
16
M Huch, L Dollé. The plastic cellular states of liver cells: are EpCAM and Lgr5 fit for purpose?. Hepatology 2016; 64(2): 652–662 https://doi.org/10.1002/hep.28469
17
CL Chaffer, I Brueckmann, C Scheel, AJ Kaestli, PA Wiggins, LO Rodrigues, M Brooks, F Reinhardt, Y Su, K Polyak, LM Arendt, C Kuperwasser, B Bierie, RA Weinberg. Normal and neoplastic nonstem cells can spontaneously convert to a stem-like state. Proc Natl Acad Sci USA 2011; 108(19): 7950–7955 https://doi.org/10.1073/pnas.1102454108
18
K Fekir, H Dubois-Pot-Schneider, R Désert, Y Daniel, D Glaise, C Rauch, F Morel, B Fromenty, O Musso, F Cabillic, A Corlu. Retrodifferentiation of human tumor hepatocytes to stem cells leads to metabolic reprogramming and chemoresistance. Cancer Res 2019; 79(8): 1869–1883 https://doi.org/10.1158/0008-5472.CAN-18-2110
19
XF Li, C Chen, DM Xiang, L Qu, W Sun, XY Lu, TF Zhou, SZ Chen, BF Ning, Z Cheng, MY Xia, WF Shen, W Yang, W Wen, TKW Lee, WM Cong, HY Wang, J Ding. Chronic inflammation-elicited liver progenitor cell conversion to liver cancer stem cell with clinical significance. Hepatology 2017; 66(6): 1934–1951 https://doi.org/10.1002/hep.29372
20
T Matsumoto, A Takai, Y Eso, K Kinoshita, T Manabe, H Seno, T Chiba, H Marusawa. Proliferating EpCAM-positive ductal cells in the inflamed liver give rise to hepatocellular carcinoma. Cancer Res 2017; 77(22): 6131–6143 https://doi.org/10.1158/0008-5472.CAN-17-1800
21
CH Ang, SH Hsu, F Guo, CT Tan, VC Yu, JE Visvader, PKH Chow, NY Fu. Lgr5+ pericentral hepatocytes are self-maintained in normal liver regeneration and susceptible to hepatocarcinogenesis. Proc Natl Acad Sci USA 2019; 116(39): 19530–19540 https://doi.org/10.1073/pnas.1908099116
22
YM Tsui, LK Chan, IO Ng. Cancer stemness in hepatocellular carcinoma: mechanisms and translational potential. Br J Cancer 2020; 122(10): 1428–1440 https://doi.org/10.1038/s41416-020-0823-9
23
TK Lee, XY Guan, S Ma. Cancer stem cells in hepatocellular carcinoma — from origin to clinical implications. Nat Rev Gastroenterol Hepatol 2022; 19(1): 26–44 https://doi.org/10.1038/s41575-021-00508-3
24
L Mishra, T Banker, J Murray, S Byers, A Thenappan, AR He, K Shetty, L Johnson, EP Reddy. Liver stem cells and hepatocellular carcinoma. Hepatology 2009; 49(1): 318–329 https://doi.org/10.1002/hep.22704
25
JW Jang, Y Song, SH Kim, JS Kim, KM Kim, EK Choi, J Kim, HR Seo. CD133 confers cancer stem-like cell properties by stabilizing EGFR-AKT signaling in hepatocellular carcinoma. Cancer Lett 2017; 389: 1–10 https://doi.org/10.1016/j.canlet.2016.12.023
26
ZF Yang, DW Ho, MN Ng, CK Lau, WC Yu, P Ngai, PWK Chu, CT Lam, RTP Poon, ST Fan. Significance of CD90+ cancer stem cells in human liver cancer. Cancer Cell 2008; 13(2): 153–166 https://doi.org/10.1016/j.ccr.2008.01.013
27
K Mima, H Okabe, T Ishimoto, H Hayashi, S Nakagawa, H Kuroki, M Watanabe, T Beppu, M Tamada, O Nagano, H Saya, H Baba. CD44s regulates the TGF-β-mediated mesenchymal phenotype and is associated with poor prognosis in patients with hepatocellular carcinoma. Cancer Res 2012; 72(13): 3414–3423 https://doi.org/10.1158/0008-5472.CAN-12-0299
28
T Yamashita, M Forgues, W Wang, JW Kim, Q Ye, H Jia, A Budhu, KA Zanetti, Y Chen, LX Qin, ZY Tang, XW Wang. EpCAM and α-fetoprotein expression defines novel prognostic subtypes of hepatocellular carcinoma. Cancer Res 2008; 68(5): 1451–1461 https://doi.org/10.1158/0008-5472.CAN-07-6013
29
N Haraguchi, H Ishii, K Mimori, F Tanaka, M Ohkuma, HM Kim, H Akita, D Takiuchi, H Hatano, H Nagano, GF Barnard, Y Doki, M Mori. CD13 is a therapeutic target in human liver cancer stem cells. J Clin Invest 2010; 120(9): 3326–3339 https://doi.org/10.1172/JCI42550
30
TKW Lee, VCH Cheung, P Lu, EYT Lau, S Ma, KH Tang, M Tong, J Lo, IOL Ng. Blockade of CD47-mediated cathepsin S/protease-activated receptor 2 signaling provides a therapeutic target for hepatocellular carcinoma. Hepatology 2014; 60(1): 179–191 https://doi.org/10.1002/hep.27070
31
X Xu, RF Liu, X Zhang, LY Huang, F Chen, QL Fei, ZG Han. DLK1 as a potential target against cancer stem/progenitor cells of hepatocellular carcinoma. Mol Cancer Ther 2012; 11(3): 629–638 https://doi.org/10.1158/1535-7163.MCT-11-0531
32
S Liu, N Li, X Yu, X Xiao, K Cheng, J Hu, J Wang, D Zhang, S Cheng, S Liu. Expression of intercellular adhesion molecule 1 by hepatocellular carcinoma stem cells and circulating tumor cells. Gastroenterology 2013; 144(5): 1031–1041.e10 https://doi.org/10.1053/j.gastro.2013.01.046
33
W Zhao, L Wang, H Han, K Jin, N Lin, T Guo, Y Chen, H Cheng, F Lu, W Fang, Y Wang, B Xing, Z Zhang. 1B50-1, a mAb raised against recurrent tumor cells, targets liver tumor-initiating cells by binding to the calcium channel α2δ1 subunit. Cancer Cell 2013; 23(4): 541–556 https://doi.org/10.1016/j.ccr.2013.02.025
34
T Kawai, K Yasuchika, T Ishii, H Katayama, EY Yoshitoshi, S Ogiso, S Kita, K Yasuda, K Fukumitsu, M Mizumoto, E Hatano, S Uemoto. Keratin 19, a cancer stem cell marker in human hepatocellular carcinoma. Clin Cancer Res 2015; 21(13): 3081–3091 https://doi.org/10.1158/1078-0432.CCR-14-1936
35
KH Tang, S Ma, TK Lee, YP Chan, PS Kwan, CM Tong, IO Ng, K Man, KF To, PB Lai, CM Lo, XY Guan, KW Chan. CD133+ liver tumor-initiating cells promote tumor angiogenesis, growth, and self-renewal through neurotensin/interleukin-8/CXCL1 signaling. Hepatology 2012; 55(3): 807–820 https://doi.org/10.1002/hep.24739
36
W Hur, JY Ryu, HU Kim, SW Hong, EB Lee, SY Lee, SK Yoon. Systems approach to characterize the metabolism of liver cancer stem cells expressing CD133. Sci Rep 2017; 7(1): 45557 https://doi.org/10.1038/srep45557
37
ZF Yang, P Ngai, DW Ho, WC Yu, MNP Ng, CK Lau, MLY Li, KH Tam, CT Lam, RTP Poon, ST Fan. Identification of local and circulating cancer stem cells in human liver cancer. Hepatology 2008; 47(3): 919–928 https://doi.org/10.1002/hep.22082
38
T Ishimoto, O Nagano, T Yae, M Tamada, T Motohara, H Oshima, M Oshima, T Ikeda, R Asaba, H Yagi, T Masuko, T Shimizu, T Ishikawa, K Kai, E Takahashi, Y Imamura, Y Baba, M Ohmura, M Suematsu, H Baba, H Saya. CD44 variant regulates redox status in cancer cells by stabilizing the xCT subunit of system xc- and thereby promotes tumor growth. Cancer Cell 2011; 19(3): 387–400 https://doi.org/10.1016/j.ccr.2011.01.038
39
JW Kim, Q Ye, M Forgues, Y Chen, A Budhu, J Sime, LJ Hofseth, R Kaul, XW Wang. Cancer-associated molecular signature in the tissue samples of patients with cirrhosis. Hepatology 2004; 39(2): 518–527 https://doi.org/10.1002/hep.20053
40
T Kawai, K Yasuchika, S Seo, T Higashi, T Ishii, Y Miyauchi, H Kojima, R Yamaoka, H Katayama, EY Yoshitoshi, S Ogiso, S Kita, K Yasuda, K Fukumitsu, Y Nakamoto, E Hatano, S Uemoto. Identification of keratin 19-positive cancer stem cells associating human hepatocellular carcinoma using 18F-fluorodeoxyglucose positron emission tomography. Clin Cancer Res 2017; 23(6): 1450–1460 https://doi.org/10.1158/1078-0432.CCR-16-0871
41
N Wang, MY Li, Y Liu, J Yu, J Ren, Z Zheng, S Wang, S Yang, SL Yang, LP Liu, BG Hu, CC Chong, JL Merchant, PB Lai, GG Chen. ZBP-89 negatively regulates self-renewal of liver cancer stem cells via suppression of Notch1 signaling pathway. Cancer Lett 2020; 472: 70–80 https://doi.org/10.1016/j.canlet.2019.12.026
42
N Wang, S Wang, SL Yang, LP Liu, MY Li, PBS Lai, GG Chen. Targeting ZBP-89 for the treatment of hepatocellular carcinoma. Expert Opin Ther Targets 2018; 22(10): 817–822 https://doi.org/10.1080/14728222.2018.1516753
PH Chang, K Sekine, HM Chao, SH Hsu, E Chern. Chitosan promotes cancer progression and stem cell properties in association with Wnt signaling in colon and hepatocellular carcinoma cells. Sci Rep 2017; 8(1): 45751 https://doi.org/10.1038/srep45751
46
Z Fan, J Duan, L Wang, S Xiao, L Li, X Yan, W Yao, L Wu, S Zhang, Y Zhang, Y Li, X Zhu, Y Hu, D Zhang, S Jiao, X Xu. PTK2 promotes cancer stem cell traits in hepatocellular carcinoma by activating Wnt/β-catenin signaling. Cancer Lett 2019; 450: 132–143 https://doi.org/10.1016/j.canlet.2019.02.040
47
M Ram Makena, H Gatla, D Verlekar, SK Sukhavasi, MC Pandey, K Pramanik. Wnt/β-catenin signaling: the culprit in pancreatic carcinogenesis and therapeutic resistance. Int J Mol Sci 2019; 20(17): 4242 https://doi.org/10.3390/ijms20174242
48
T Yamashita, J Ji, A Budhu, M Forgues, W Yang, HY Wang, H Jia, Q Ye, LX Qin, E Wauthier, LM Reid, H Minato, M Honda, S Kaneko, ZY Tang, XW Wang. EpCAM-positive hepatocellular carcinoma cells are tumor-initiating cells with stem/progenitor cell features. Gastroenterology 2009; 136(3): 1012–1024 https://doi.org/10.1053/j.gastro.2008.12.004
49
S Ma, KW Chan, L Hu, TK Lee, JY Wo, IO Ng, BJ Zheng, XY Guan. Identification and characterization of tumorigenic liver cancer stem/progenitor cells. Gastroenterology 2007; 132(7): 2542–2556 https://doi.org/10.1053/j.gastro.2007.04.025
50
J Zhu, H Yu, S Chen, P Yang, Z Dong, Y Ling, H Tang, S Bai, W Yang, L Tang, F Shen, H Wang, W Wen. Prognostic significance of combining high mobility group Box-1 and OV-6 expression in hepatocellular carcinoma. Sci China Life Sci 2018; 61(8): 912–923 https://doi.org/10.1007/s11427-017-9188-x
51
S Mokkapati, K Niopek, L Huang, KJ Cunniff, EC Ruteshouser, M deCaestecker, MJ Finegold, V Huff. β-catenin activation in a novel liver progenitor cell type is sufficient to cause hepatocellular carcinoma and hepatoblastoma. Cancer Res 2014; 74(16): 4515–4525 https://doi.org/10.1158/0008-5472.CAN-13-3275
52
D Xiang, Z Cheng, H Liu, X Wang, T Han, W Sun, X Li, W Yang, C Chen, M Xia, N Liu, S Yin, G Jin, T Lee, L Dong, H Hu, H Wang, J Ding. Shp2 promotes liver cancer stem cell expansion by augmenting β-catenin signaling and predicts chemotherapeutic response of patients. Hepatology 2017; 65(5): 1566–1580 https://doi.org/10.1002/hep.28919
53
HW Leung, CON Leung, EY Lau, KPS Chung, EH Mok, MML Lei, RWH Leung, M Tong, VW Keng, C Ma, Q Zhao, IOL Ng, S Ma, TK Lee. EPHB2 activates β-catenin to enhance cancer stem cell properties and drive sorafenib resistance in hepatocellular carcinoma. Cancer Res 2021; 81(12): 3229–3240 https://doi.org/10.1158/0008-5472.CAN-21-0184
54
T Yamashita, A Budhu, M Forgues, XW Wang. Activation of hepatic stem cell marker EpCAM by Wnt-beta-catenin signaling in hepatocellular carcinoma. Cancer Res 2007; 67(22): 10831–10839 https://doi.org/10.1158/0008-5472.CAN-07-0908
55
DC Kahraman, T Kahraman, R Cetin-Atalay. Targeting PI3K/Akt/mTOR pathway identifies differential expression and functional role of IL8 in liver cancer stem cell enrichment. Mol Cancer Ther 2019; 18(11): 2146–2157 https://doi.org/10.1158/1535-7163.MCT-19-0004
56
XQ Wang, W Zhang, ELH Lui, Y Zhu, P Lu, X Yu, J Sun, S Yang, RTP Poon, ST Fan. Notch1-Snail1-E-cadherin pathway in metastatic hepatocellular carcinoma. Int J Cancer 2012; 131(3): E163–E172 https://doi.org/10.1002/ijc.27336
57
S Xiao, RM Chang, MY Yang, X Lei, X Liu, WB Gao, JL Xiao, LY Yang. Actin-like 6A predicts poor prognosis of hepatocellular carcinoma and promotes metastasis and epithelial-mesenchymal transition. Hepatology 2016; 63(4): 1256–1271 https://doi.org/10.1002/hep.28417
58
P Zhu, Y Wang, Y Du, L He, G Huang, G Zhang, X Yan, Z Fan. C8orf4 negatively regulates self-renewal of liver cancer stem cells via suppression of NOTCH2 signalling. Nat Commun 2015; 6(1): 7122 https://doi.org/10.1038/ncomms8122
59
R Wang, Y Li, A Tsung, H Huang, Q Du, M Yang, M Deng, S Xiong, X Wang, L Zhang, DA Geller, B Cheng, TR Billiar. iNOS promotes CD24+CD133+ liver cancer stem cell phenotype through a TACE/ADAM17-dependent Notch signaling pathway. Proc Natl Acad Sci USA 2018; 115(43): E10127–E10136 https://doi.org/10.1073/pnas.1722100115
60
L Lin, R Amin, GI Gallicano, E Glasgow, W Jogunoori, JM Jessup, M Zasloff, JL Marshall, K Shetty, L Johnson, L Mishra, AR He. The STAT3 inhibitor NSC 74859 is effective in hepatocellular cancers with disrupted TGF-β signaling. Oncogene 2009; 28(7): 961–972 https://doi.org/10.1038/onc.2008.448
61
C Wang, W Yang, HX Yan, T Luo, J Zhang, L Tang, FQ Wu, HL Zhang, LX Yu, LY Zheng, YQ Li, W Dong, YQ He, Q Liu, SS Zou, Y Lin, L Hu, Z Li, MC Wu, HY Wang. Hepatitis B virus X (HBx) induces tumorigenicity of hepatic progenitor cells in 3,5-diethoxycarbonyl-1,4-dihydrocollidine-treated HBx transgenic mice. Hepatology 2012; 55(1): 108–120 https://doi.org/10.1002/hep.24675
62
TK Lee, A Castilho, VC Cheung, KH Tang, S Ma, IO Ng. CD24+ liver tumor-initiating cells drive self-renewal and tumor initiation through STAT3-mediated NANOG regulation. Cell Stem Cell 2011; 9(1): 50–63 https://doi.org/10.1016/j.stem.2011.06.005
63
C Xie, J Zhu, X Wang, J Chen, S Geng, J Wu, C Zhong, X Li. Tobacco smoke induced hepatic cancer stem cell-like properties through IL-33/p38 pathway. J Exp Clin Cancer Res 2019; 38(1): 39 https://doi.org/10.1186/s13046-019-1052-z
64
TB Toh, JJ Lim, L Hooi, MBMA Rashid, EK Chow. Targeting Jak/Stat pathway as a therapeutic strategy against SP/CD44+ tumorigenic cells in Akt/β-catenin-driven hepatocellular carcinoma. J Hepatol 2020; 72(1): 104–118 https://doi.org/10.1016/j.jhep.2019.08.035
65
G Schiavoni, L Gabriele, F Mattei. The tumor microenvironment: a pitch for multiple players. Front Oncol 2013; 3: 90 https://doi.org/10.3389/fonc.2013.00090
66
T Fang, H Lv, G Lv, T Li, C Wang, Q Han, L Yu, B Su, L Guo, S Huang, D Cao, L Tang, S Tang, M Wu, W Yang, H Wang. Tumor-derived exosomal miR-1247-3p induces cancer-associated fibroblast activation to foster lung metastasis of liver cancer. Nat Commun 2018; 9(1): 191 https://doi.org/10.1038/s41467-017-02583-0
67
B Tian, Q Luo, Y Ju, G Song. A soft matrix enhances the cancer stem cell phenotype of HCC cells. Int J Mol Sci 2019; 20(11): 2831 https://doi.org/10.3390/ijms20112831
68
JH Loong, TL Wong, M Tong, R Sharma, L Zhou, KY Ng, HJ Yu, CH Li, K Man, CM Lo, XY Guan, TK Lee, JP Yun, SK Ma. Glucose deprivation-induced aberrant FUT1-mediated fucosylation drives cancer stemness in hepatocellular carcinoma. J Clin Invest 2021; 131(11): e143377 https://doi.org/10.1172/JCI143377
69
Z Liu, X Dai, T Wang, C Zhang, W Zhang, W Zhang, Q Zhang, K Wu, F Liu, Y Liu, J Wu. Hepatitis B virus PreS1 facilitates hepatocellular carcinoma development by promoting appearance and self-renewal of liver cancer stem cells. Cancer Lett 2017; 400: 149–160 https://doi.org/10.1016/j.canlet.2017.04.017
70
WB Ding, MC Wang, J Yu, G Huang, DP Sun, L Liu, JN Zhang, Y Yang, H Liu, WP Zhou, F Yang, SX Yuan. HBV/pregenomic RNA increases the stemness and promotes the development of HBV-related HCC through reciprocal regulation with insulin-like growth factor 2 mRNA-binding protein 3. Hepatology 2021; 74(3): 1480–1495 https://doi.org/10.1002/hep.31850
71
EYT Lau, J Lo, BYL Cheng, MKF Ma, JMF Lee, JKY Ng, S Chai, CH Lin, SY Tsang, S Ma, IOL Ng, TKW Lee. Cancer-associated fibroblasts regulate tumor-initiating cell plasticity in hepatocellular carcinoma through c-Met/FRA1/HEY1 signaling. Cell Rep 2016; 15(6): 1175–1189 https://doi.org/10.1016/j.celrep.2016.04.019
72
C Liu, L Liu, X Chen, J Cheng, H Zhang, C Zhang, J Shan, J Shen, C Qian. LSD1 stimulates cancer-associated fibroblasts to drive notch3-dependent self-renewal of liver cancer stem-like cells. Cancer Res 2018; 78(4): 938–949 https://doi.org/10.1158/0008-5472.CAN-17-1236
73
S Xiong, R Wang, Q Chen, J Luo, J Wang, Z Zhao, Y Li, Y Wang, X Wang, B Cheng. Cancer-associated fibroblasts promote stem cell-like properties of hepatocellular carcinoma cells through IL-6/STAT3/Notch signaling. Am J Cancer Res 2018; 8(2): 302–316
74
B Tavora, T Mederer, KJ Wessel, S Ruffing, M Sadjadi, M Missmahl, BN Ostendorf, X Liu, JY Kim, O Olsen, AL Welm, H Goodarzi, SF Tavazoie. Tumoural activation of TLR3-SLIT2 axis in endothelium drives metastasis. Nature 2020; 586(7828): 299–304 https://doi.org/10.1038/s41586-020-2774-y
75
A Conigliaro, V Costa, A Lo Dico, L Saieva, S Buccheri, F Dieli, M Manno, S Raccosta, C Mancone, M Tripodi, G De Leo, R Alessandro. CD90+ liver cancer cells modulate endothelial cell phenotype through the release of exosomes containing H19 lncRNA. Mol Cancer 2015; 14(1): 155 https://doi.org/10.1186/s12943-015-0426-x
76
H Yao, N Liu, MC Lin, J Zheng. Positive feedback loop between cancer stem cells and angiogenesis in hepatocellular carcinoma. Cancer Lett 2016; 379(2): 213–219 https://doi.org/10.1016/j.canlet.2016.03.014
S Wan, E Zhao, I Kryczek, L Vatan, A Sadovskaya, G Ludema, DM Simeone, W Zou, TH Welling. Tumor-associated macrophages produce interleukin 6 and signal via STAT3 to promote expansion of human hepatocellular carcinoma stem cells. Gastroenterology 2014; 147(6): 1393–1404 https://doi.org/10.1053/j.gastro.2014.08.039
79
Y Chen, H Wen, C Zhou, Q Su, Y Lin, Y Xie, Y Huang, Q Qiu, J Lin, X Huang, W Tan, C Min, C Wang. TNF-α derived from M2 tumor-associated macrophages promotes epithelial-mesenchymal transition and cancer stemness through the Wnt/β-catenin pathway in SMMC-7721 hepatocellular carcinoma cells. Exp Cell Res 2019; 378(1): 41–50 https://doi.org/10.1016/j.yexcr.2019.03.005
80
QM Fan, YY Jing, GF Yu, XR Kou, F Ye, L Gao, R Li, QD Zhao, Y Yang, ZH Lu, LX Wei. Tumor-associated macrophages promote cancer stem cell-like properties via transforming growth factor-beta1-induced epithelial-mesenchymal transition in hepatocellular carcinoma. Cancer Lett 2014; 352(2): 160–168 https://doi.org/10.1016/j.canlet.2014.05.008
81
YC Liu, CT Yeh, KH Lin. Cancer stem cell functions in hepatocellular carcinoma and comprehensive therapeutic strategies. Cells 2020; 9(6): 1331 https://doi.org/10.3390/cells9061331
82
J Chen, DX Zheng, XJ Yu, HW Sun, YT Xu, YJ Zhang, J Xu. Macrophages induce CD47 upregulation via IL-6 and correlate with poor survival in hepatocellular carcinoma patients. OncoImmunology 2019; 8(11): e1652540 https://doi.org/10.1080/2162402X.2019.1652540
83
LY Ye, W Chen, XL Bai, XY Xu, Q Zhang, XF Xia, X Sun, GG Li, QD Hu, QH Fu, TB Liang. Hypoxia-induced epithelial-to-mesenchymal transition in hepatocellular carcinoma induces an immunosuppressive tumor microenvironment to promote metastasis. Cancer Res 2016; 76(4): 818–830 https://doi.org/10.1158/0008-5472.CAN-15-0977
84
SL Zhou, D Yin, ZQ Hu, CB Luo, ZJ Zhou, HY Xin, XR Yang, YH Shi, Z Wang, XW Huang, Y Cao, J Fan, J Zhou. A positive feedback loop between cancer stem-like cells and tumor-associated neutrophils controls hepatocellular carcinoma progression. Hepatology 2019; 70(4): 1214–1230 https://doi.org/10.1002/hep.30630
B Chaudhary, E Elkord. Regulatory T cells in the tumor microenvironment and cancer progression: role and therapeutic targeting. Vaccines (Basel) 2016; 4(3): 28 https://doi.org/10.3390/vaccines4030028
87
C Shi, Y Chen, Y Chen, Y Yang, W Bing, J Qi. CD4+ CD25+ regulatory T cells promote hepatocellular carcinoma invasion via TGF-β1-induced epithelial-mesenchymal transition. OncoTargets Ther 2018; 12: 279–289 https://doi.org/10.2147/OTT.S172417
T Yang, W Zhang, L Wang, C Xiao, L Wang, Y Gong, D Huang, B Guo, Q Li, Y Xiang, Y Nan. Co-culture of dendritic cells and cytokine-induced killer cells effectively suppresses liver cancer stem cell growth by inhibiting pathways in the immune system. BMC Cancer 2018; 18(1): 984 https://doi.org/10.1186/s12885-018-4871-y
90
G Wang, J Xu, J Zhao, W Yin, D Liu, W Chen, SX Hou. Arf1-mediated lipid metabolism sustains cancer cells and its ablation induces anti-tumor immune responses in mice. Nat Commun 2020; 11(1): 220 https://doi.org/10.1038/s41467-019-14046-9
91
M Zhong, C Zhong, W Cui, G Wang, G Zheng, L Li, J Zhang, R Ren, H Gao, T Wang, X Li, J Che, E Gohda. Induction of tolerogenic dendritic cells by activated TGF-β/Akt/Smad2 signaling in RIG-I-deficient stemness-high human liver cancer cells. BMC Cancer 2019; 19(1): 439 https://doi.org/10.1186/s12885-019-5670-9
92
AD Pardee, J Shi, LH Butterfield. Tumor-derived α-fetoprotein impairs the differentiation and T cell stimulatory activity of human dendritic cells. J Immunol 2014; 193(11): 5723–5732 https://doi.org/10.4049/jimmunol.1400725
93
V Shankaran, H Ikeda, AT Bruce, JM White, PE Swanson, LJ Old, RD Schreiber. IFNgamma and lymphocytes prevent primary tumour development and shape tumour immunogenicity. Nature 2001; 410(6832): 1107–1111 https://doi.org/10.1038/35074122
94
H Lv, G Lv, C Chen, Q Zong, G Jiang, D Ye, X Cui, Y He, W Xiang, Q Han, L Tang, W Yang, H Wang. NAD+ metabolism maintains inducible PD-L1 expression to drive tumor immune evasion. Cell Metab 2021; 33(1): 110–127.e5 https://doi.org/10.1016/j.cmet.2020.10.021
95
X Dai, Y Guo, Y Hu, X Bao, X Zhu, Q Fu, H Zhang, Z Tong, L Liu, Y Zheng, P Zhao, W Fang. Immunotherapy for targeting cancer stem cells in hepatocellular carcinoma. Theranostics 2021; 11(7): 3489–3501 https://doi.org/10.7150/thno.54648
96
JM Hsu, W Xia, YH Hsu, LC Chan, WH Yu, JH Cha, CT Chen, HW Liao, CW Kuo, KH Khoo, JL Hsu, CW Li, SO Lim, SS Chang, YC Chen, GX Ren, MC Hung. STT3-dependent PD-L1 accumulation on cancer stem cells promotes immune evasion. Nat Commun 2018; 9(1): 1908 https://doi.org/10.1038/s41467-018-04313-6
97
BJ Morrison, JC Steel, JC Morris. Reduction of MHC-I expression limits T-lymphocyte-mediated killing of cancer-initiating cells. BMC Cancer 2018; 18(1): 469 https://doi.org/10.1186/s12885-018-4389-3
98
H Dianat-Moghadam, M Rokni, F Marofi, Y Panahi, M Yousefi. Natural killer cell-based immunotherapy: from transplantation toward targeting cancer stem cells. J Cell Physiol 2018; 234(1): 259–273 https://doi.org/10.1002/jcp.26878
99
PF Cheung, CW Yip, NC Wong, DY Fong, LW Ng, AM Wan, CK Wong, TT Cheung, IO Ng, RT Poon, ST Fan, ST Cheung. Granulin-epithelin precursor renders hepatocellular carcinoma cells resistant to natural killer cytotoxicity. Cancer Immunol Res 2014; 2(12): 1209–1219 https://doi.org/10.1158/2326-6066.CIR-14-0096
100
KH Lam, S Ma. Noncellular components in the liver cancer stem cell niche: biology and potential clinical implications. Hepatology 2023; 78(3): 991–1005 https://doi.org/10.1002/hep.32629
101
Y You, Q Zheng, Y Dong, X Xie, Y Wang, S Wu, L Zhang, Y Wang, T Xue, Z Wang, R Chen, Y Wang, J Cui, Z Ren. Matrix stiffness-mediated effects on stemness characteristics occurring in HCC cells. Oncotarget 2016; 7(22): 32221–32231 https://doi.org/10.18632/oncotarget.8515
102
K Kohga, T Tatsumi, T Takehara, H Tsunematsu, S Shimizu, M Yamamoto, A Sasakawa, T Miyagi, N Hayashi. Expression of CD133 confers malignant potential by regulating metalloproteinases in human hepatocellular carcinoma. J Hepatol 2010; 52(6): 872–879 https://doi.org/10.1016/j.jhep.2009.12.030
103
W Zhao, M Lv, X Yang, J Zhou, B Xing, Z Zhang. Liver tumor-initiating cells initiate the formation of a stiff cancer stem cell microenvironment niche by secreting LOX. Carcinogenesis 2022; 43(8): 766–778 https://doi.org/10.1093/carcin/bgac035
104
CP Cui, CC Wong, AK Kai, DW Ho, EY Lau, YM Tsui, LK Chan, TT Cheung, KS Chok, ACY Chan, RC Lo, JM Lee, TK Lee, IOL Ng. SENP1 promotes hypoxia-induced cancer stemness by HIF-1α deSUMOylation and SENP1/HIF-1α positive feedback loop. Gut 2017; 66(12): 2149–2159 https://doi.org/10.1136/gutjnl-2016-313264
105
G Liu, Q Luo, H Li, Q Liu, Y Ju, G Song. Increased oxidative phosphorylation is required for stemness maintenance in liver cancer stem cells from hepatocellular carcinoma cell line HCCLM3 cells. Int J Mol Sci 2020; 21(15): 5276 https://doi.org/10.3390/ijms21155276
106
Y Liu, H Ren, Y Zhou, L Shang, Y Zhang, F Yang, X Shi. The hypoxia conditioned mesenchymal stem cells promote hepatocellular carcinoma progression through YAP mediated lipogenesis reprogramming. J Exp Clin Cancer Res 2019; 38(1): 228 https://doi.org/10.1186/s13046-019-1219-7
107
S Ling, Q Shan, Q Zhan, Q Ye, P Liu, S Xu, X He, J Ma, J Xiang, G Jiang, X Wen, Z Feng, Y Wu, T Feng, L Xu, K Chen, X Zhang, R Wei, C Zhang, B Cen, H Xie, P Song, J Liu, S Zheng, X Xu. USP22 promotes hypoxia-induced hepatocellular carcinoma stemness by a HIF1α/USP22 positive feedback loop upon TP53 inactivation. Gut 2020; 69(7): 1322–1334 https://doi.org/10.1136/gutjnl-2019-319616
108
A Chisari, I Golán, S Campisano, C Gélabert, A Moustakas, P Sancho, L Caja. Glucose and amino acid metabolic dependencies linked to stemness and metastasis in different aggressive cancer types. Front Pharmacol 2021; 12: 723798 https://doi.org/10.3389/fphar.2021.723798
109
SH Lin, T Liu, X Ming, Z Tang, L Fu, P Schmitt-Kopplin, B Kanawati, XY Guan, Z Cai. Regulatory role of hexosamine biosynthetic pathway on hepatic cancer stem cell marker CD133 under low glucose conditions. Sci Rep 2016; 6(1): 21184 https://doi.org/10.1038/srep21184
110
H Fan, H Zhang, PE Pascuzzi, O Andrisani. Hepatitis B virus X protein induces EpCAM expression via active DNA demethylation directed by RelA in complex with EZH2 and TET2. Oncogene 2016; 35(6): 715–726 https://doi.org/10.1038/onc.2015.122
111
N Ali, H Allam, R May, SM Sureban, MS Bronze, T Bader, S Umar, S Anant, CW Houchen. Hepatitis C virus-induced cancer stem cell-like signatures in cell culture and murine tumor xenografts. J Virol 2011; 85(23): 12292–12303 https://doi.org/10.1128/JVI.05920-11
112
M Zhu, W Li, Y Lu, X Dong, B Lin, Y Chen, X Zhang, J Guo, M Li. HBx drives alpha fetoprotein expression to promote initiation of liver cancer stem cells through activating PI3K/AKT signal pathway. Int J Cancer 2017; 140(6): 1346–1355 https://doi.org/10.1002/ijc.30553
113
S Shrivastava, A Mukherjee, R Ray, RB Ray. Hepatitis C virus induces interleukin-1β (IL-1β)/IL-18 in circulatory and resident liver macrophages. J Virol 2013; 87(22): 12284–12290 https://doi.org/10.1128/JVI.01962-13
114
X Lin, S Zuo, R Luo, Y Li, G Yu, Y Zou, Y Zhou, Z Liu, Y Liu, Y Hu, Y Xie, W Fang, Z Liu. HBX-induced miR-5188 impairs FOXO1 to stimulate β-catenin nuclear translocation and promotes tumor stemness in hepatocellular carcinoma. Theranostics 2019; 9(25): 7583–7598 https://doi.org/10.7150/thno.37717
115
DB Uthaya Kumar, CL Chen, JC Liu, DE Feldman, LS Sher, S French, J DiNorcia, SW French, BV Naini, S Junrungsee, VG Agopian, A Zarrinpar, K Machida. TLR4 signaling via NANOG cooperates with STAT3 to activate twist1 and promote formation of tumor-initiating stem-like cells in livers of mice. Gastroenterology 2016; 150(3): 707–719 https://doi.org/10.1053/j.gastro.2015.11.002
116
H Fan, Z Cui, H Zhang, SK Mani, A Diab, L Lefrancois, N Fares, P Merle, O Andrisani. DNA demethylation induces SALL4 gene re-expression in subgroups of hepatocellular carcinoma associated with Hepatitis B or C virus infection. Oncogene 2017; 36(17): 2435–2445 https://doi.org/10.1038/onc.2016.399
117
ML Broz, MF Krummel. The emerging understanding of myeloid cells as partners and targets in tumor rejection. Cancer Immunol Res 2015; 3(4): 313–319 https://doi.org/10.1158/2326-6066.CIR-15-0041
118
DI Gabrilovich, S Ostrand-Rosenberg, V Bronte. Coordinated regulation of myeloid cells by tumours. Nat Rev Immunol 2012; 12(4): 253–268 https://doi.org/10.1038/nri3175
119
C Engblom, C Pfirschke, MJ Pittet. The role of myeloid cells in cancer therapies. Nat Rev Cancer 2016; 16(7): 447–462 https://doi.org/10.1038/nrc.2016.54
120
R Gentek, K Molawi, MH Sieweke. Tissue macrophage identity and self-renewal. Immunol Rev 2014; 262(1): 56–73 https://doi.org/10.1111/imr.12224
121
K Wu, K Lin, X Li, X Yuan, P Xu, P Ni, D Xu. Redefining tumor-associated macrophage subpopulations and functions in the tumor microenvironment. Front Immunol 2020; 11: 1731 https://doi.org/10.3389/fimmu.2020.01731
122
S Jhunjhunwala, C Hammer, L Delamarre. Antigen presentation in cancer: insights into tumour immunogenicity and immune evasion. Nat Rev Cancer 2021; 21(5): 298–312 https://doi.org/10.1038/s41568-021-00339-z
123
P Xiao, X Long, L Zhang, Y Ye, J Guo, P Liu, R Zhang, J Ning, W Yu, F Wei, J Yu. Neurotensin/IL-8 pathway orchestrates local inflammatory response and tumor invasion by inducing M2 polarization of tumor-associated macrophages and epithelial-mesenchymal transition of hepatocellular carcinoma cells. OncoImmunology 2018; 7(7): e1440166 https://doi.org/10.1080/2162402X.2018.1440166
124
F Zhu, X Li, S Chen, Q Zeng, Y Zhao, F Luo. Tumor-associated macrophage or chemokine ligand CCL17 positively regulates the tumorigenesis of hepatocellular carcinoma. Med Oncol 2016; 33(2): 17 https://doi.org/10.1007/s12032-016-0729-9
125
W Yan, X Liu, H Ma, H Zhang, X Song, L Gao, X Liang, C Ma. Tim-3 fosters HCC development by enhancing TGF-β-mediated alternative activation of macrophages. Gut 2015; 64(10): 1593–1604 https://doi.org/10.1136/gutjnl-2014-307671
126
XT Fu, Z Dai, K Song, ZJ Zhang, ZJ Zhou, SL Zhou, YM Zhao, YS Xiao, QM Sun, ZB Ding, J Fan. Macrophage-secreted IL-8 induces epithelial-mesenchymal transition in hepatocellular carcinoma cells by activating the JAK2/STAT3/Snail pathway. Int J Oncol 2015; 46(2): 587–596 https://doi.org/10.3892/ijo.2014.2761
127
ZP Peng, ZZ Jiang, HF Guo, MM Zhou, YF Huang, WR Ning, JH Huang, L Zheng, Y Wu. Glycolytic activation of monocytes regulates the accumulation and function of neutrophils in human hepatocellular carcinoma. J Hepatol 2020; 73(4): 906–917 https://doi.org/10.1016/j.jhep.2020.05.004
128
Y Wang, B Wang, S Xiao, Y Li, Q Chen. miR-125a/b inhibits tumor-associated macrophages mediated in cancer stem cells of hepatocellular carcinoma by targeting CD90. J Cell Biochem 2019; 120(3): 3046–3055 https://doi.org/10.1002/jcb.27436
129
D Iliopoulos, HA Hirsch, K Struhl. An epigenetic switch involving NF-κB, Lin28, Let-7 MicroRNA, and IL6 links inflammation to cell transformation. Cell 2009; 139(4): 693–706 https://doi.org/10.1016/j.cell.2009.10.014
130
AA Barkal, RE Brewer, M Markovic, M Kowarsky, SA Barkal, BW Zaro, V Krishnan, J Hatakeyama, O Dorigo, LJ Barkal, IL Weissman. CD24 signalling through macrophage Siglec-10 is a target for cancer immunotherapy. Nature 2019; 572(7769): 392–396 https://doi.org/10.1038/s41586-019-1456-0
131
K Arvanitakis, I Mitroulis, G Germanidis. Tumor-associated neutrophils in hepatocellular carcinoma pathogenesis, prognosis, and therapy. Cancers (Basel) 2021; 13(12): 2899 https://doi.org/10.3390/cancers13122899
132
M Song, J He, QZ Pan, J Yang, J Zhao, YJ Zhang, Y Huang, Y Tang, Q Wang, J He, J Gu, Y Li, S Chen, J Zeng, ZQ Zhou, C Yang, Y Han, H Chen, T Xiang, DS Weng, JC Xia. Cancer-associated fibroblast-mediated cellular crosstalk supports hepatocellular carcinoma progression. Hepatology 2021; 73(5): 1717–1735 https://doi.org/10.1002/hep.31792
133
T Ma, BW Renz, M Ilmer, D Koch, Y Yang, J Werner, AV Bazhin. Myeloid-derived suppressor cells in solid tumors. Cells 2022; 11(2): 310 https://doi.org/10.3390/cells11020310
134
E Tcyganov, J Mastio, E Chen, DI Gabrilovich. Plasticity of myeloid-derived suppressor cells in cancer. Curr Opin Immunol 2018; 51: 76–82 https://doi.org/10.1016/j.coi.2018.03.009
135
S Ostrand-Rosenberg. Myeloid-derived suppressor cells: more mechanisms for inhibiting antitumor immunity. Cancer Immunol Immunother 2010; 59(10): 1593–1600 https://doi.org/10.1007/s00262-010-0855-8
136
M Xu, Z Zhao, J Song, X Lan, S Lu, M Chen, Z Wang, W Chen, X Fan, F Wu, L Chen, J Tu, J Ji. Interactions between interleukin-6 and myeloid-derived suppressor cells drive the chemoresistant phenotype of hepatocellular cancer. Exp Cell Res 2017; 351(2): 142–149 https://doi.org/10.1016/j.yexcr.2017.01.008
137
WC Lee, PY Hsu, HY Hsu. Stem cell factor produced by tumor cells expands myeloid-derived suppressor cells in mice. Sci Rep 2020; 10(1): 11257 https://doi.org/10.1038/s41598-020-68061-8
138
M Liu, J Zhou, X Liu, Y Feng, W Yang, F Wu, OK Cheung, H Sun, X Zeng, W Tang, MTS Mok, J Wong, PC Yeung, PBS Lai, Z Chen, H Jin, J Chen, SL Chan, AWH Chan, KF To, JJY Sung, M Chen, AS Cheng. Targeting monocyte-intrinsic enhancer reprogramming improves immunotherapy efficacy in hepatocellular carcinoma. Gut 2020; 69(2): 365–379 https://doi.org/10.1136/gutjnl-2018-317257
139
Q He, M Liu, W Huang, X Chen, B Zhang, T Zhang, Y Wang, D Liu, M Xie, X Ji, M Sun, D Tian, L Xia. IL-1β-induced elevation of solute carrier family 7 member 11 promotes hepatocellular carcinoma metastasis through up-regulating programmed death ligand 1 and colony-stimulating factor 1. Hepatology 2021; 74(6): 3174–3193 https://doi.org/10.1002/hep.32062
140
Y Lin, Q Cai, Y Chen, T Shi, W Liu, L Mao, B Deng, Z Ying, Y Gao, H Luo, X Yang, X Huang, Y Shi, R He. CAFs shape myeloid-derived suppressor cells to promote stemness of intrahepatic cholangiocarcinoma through 5-lipoxygenase. Hepatology 2022; 75(1): 28–42 https://doi.org/10.1002/hep.32099
141
S Wang, J Sun, K Chen, P Ma, Q Lei, S Xing, Z Cao, S Sun, Z Yu, Y Liu, N Li. Perspectives of tumor-infiltrating lymphocyte treatment in solid tumors. BMC Med 2021; 19(1): 140 https://doi.org/10.1186/s12916-021-02006-4
142
GE Idos, J Kwok, N Bonthala, L Kysh, SB Gruber, C Qu. The prognostic implications of tumor infiltrating lymphocytes in colorectal cancer: a systematic review and meta-analysis. Sci Rep 2020; 10(1): 3360 https://doi.org/10.1038/s41598-020-60255-4
143
L Ren, Y Yu, L Wang, Z Zhu, R Lu, Z Yao. Hypoxia-induced CCL28 promotes recruitment of regulatory T cells and tumor growth in liver cancer. Oncotarget 2016; 7(46): 75763–75773 https://doi.org/10.18632/oncotarget.12409
144
P Yang, QJ Li, Y Feng, Y Zhang, GJ Markowitz, S Ning, Y Deng, J Zhao, S Jiang, Y Yuan, HY Wang, SQ Cheng, D Xie, XF Wang. TGF-β-miR-34a-CCL22 signaling-induced Treg cell recruitment promotes venous metastases of HBV-positive hepatocellular carcinoma. Cancer Cell 2012; 22(3): 291–303 https://doi.org/10.1016/j.ccr.2012.07.023
145
Y Kurebayashi, H Ojima, H Tsujikawa, N Kubota, J Maehara, Y Abe, M Kitago, M Shinoda, Y Kitagawa, M Sakamoto. Landscape of immune microenvironment in hepatocellular carcinoma and its additional impact on histological and molecular classification. Hepatology 2018; 68(3): 1025–1041 https://doi.org/10.1002/hep.29904
146
J Calderaro, B Rousseau, G Amaddeo, M Mercey, C Charpy, C Costentin, A Luciani, ES Zafrani, A Laurent, D Azoulay, F Lafdil, JM Pawlotsky. Programmed death ligand 1 expression in hepatocellular carcinoma: relationship with clinical and pathological features. Hepatology 2016; 64(6): 2038–2046 https://doi.org/10.1002/hep.28710
147
JM Hsu, W Xia, YH Hsu, LC Chan, WH Yu, JH Cha, CT Chen, HW Liao, CW Kuo, KH Khoo, JL Hsu, CW Li, SO Lim, SS Chang, YC Chen, GX Ren, MC Hung. STT3-dependent PD-L1 accumulation on cancer stem cells promotes immune evasion. Nat Commun 2018; 9(1): 1908 https://doi.org/10.1038/s41467-018-04313-6
148
LC Chan, CW Li, W Xia, JM Hsu, HH Lee, JH Cha, HL Wang, WH Yang, EY Yen, WC Chang, Z Zha, SO Lim, YJ Lai, C Liu, J Liu, Q Dong, Y Yang, L Sun, Y Wei, L Nie, JL Hsu, H Li, Q Ye, MM Hassan, HM Amin, AO Kaseb, X Lin, SC Wang, MC Hung. IL-6/JAK1 pathway drives PD-L1 Y112 phosphorylation to promote cancer immune evasion. J Clin Invest 2019; 129(8): 3324–3338 https://doi.org/10.1172/JCI126022
149
Z Wei, J Jia, G Heng, H Xu, J Shan, G Wang, C Liu, J Xia, H Zhou, M Wu, Z Yang, M Wang, Z Xiong, H Huang, L Liu, C Qian. Sirtuin-1/mitochondrial ribosomal protein S5 axis enhances the metabolic flexibility of liver cancer stem cells. Hepatology 2019; 70(4): 1197–1213 https://doi.org/10.1002/hep.30622
150
de Galarreta M Ruiz, E Bresnahan, P Molina-Sánchez, KE Lindblad, B Maier, D Sia, M Puigvehi, V Miguela, M Casanova-Acebes, M Dhainaut, C Villacorta-Martin, AD Singhi, A Moghe, Felden J von, Grinspan L Tal, S Wang, AO Kamphorst, SP Monga, BD Brown, A Villanueva, JM Llovet, M Merad, A Lujambio. β-catenin activation promotes immune escape and resistance to anti-PD-1 therapy in hepatocellular carcinoma. Cancer Discov 2019; 9(8): 1124–1141 https://doi.org/10.1158/2159-8290.CD-19-0074
151
GQ Zhu, Y Wang, B Wang, WR Liu, SS Dong, EB Chen, JL Cai, JL Wan, JX Du, LN Song, SP Chen, L Yu, ZJ Zhou, Z Wang, J Zhou, YH Shi, J Fan, Z Dai. Targeting HNRNPM inhibits cancer stemness and enhances antitumor immunity in Wnt-activated hepatocellular carcinoma. Cell Mol Gastroenterol Hepatol 2022; 13(5): 1413–1447 https://doi.org/10.1016/j.jcmgh.2022.02.006
152
MM Rodríguez, E Fiore, J Bayo, C Atorrasagasti, M García, A Onorato, L Domínguez, M Malvicini, G Mazzolini. 4Mu decreases CD47 expression on hepatic cancer stem cells and primes a potent antitumor T cell response induced by interleukin-12. Mol Ther 2018; 26(12): 2738–2750 https://doi.org/10.1016/j.ymthe.2018.09.012
153
ST Cheung, PFY Cheung, CKC Cheng, NCL Wong, ST Fan. Granulin-epithelin precursor and ATP-dependent binding cassette (ABC)B5 regulate liver cancer cell chemoresistance. Gastroenterology 2011; 140(1): 344–355 https://doi.org/10.1053/j.gastro.2010.07.049
154
PF Cheung, CW Yip, NC Wong, DY Fong, LW Ng, AM Wan, CK Wong, TT Cheung, IO Ng, RT Poon, ST Fan, ST Cheung. Granulin-epithelin precursor renders hepatocellular carcinoma cells resistant to natural killer cytotoxicity. Cancer Immunol Res 2014; 2(12): 1209–1219 https://doi.org/10.1158/2326-6066.CIR-14-0096
155
DJ Park, PS Sung, JH Kim, GW Lee, JW Jang, ES Jung, SH Bae, JY Choi, SK Yoon. EpCAM-high liver cancer stem cells resist natural killer cell-mediated cytotoxicity by upregulating CEACAM1. J Immunother Cancer 2020; 8(1): e000301 https://doi.org/10.1136/jitc-2019-000301
156
PF Zhang, C Gao, XY Huang, JC Lu, XJ Guo, GM Shi, JB Cai, AW Ke. Cancer cell-derived exosomal circUHRF1 induces natural killer cell exhaustion and may cause resistance to anti-PD1 therapy in hepatocellular carcinoma. Mol Cancer 2020; 19(1): 110 https://doi.org/10.1186/s12943-020-01222-5
157
Y Ma, GV Shurin, Z Peiyuan, MR Shurin. Dendritic cells in the cancer microenvironment. J Cancer 2013; 4(1): 36–44 https://doi.org/10.7150/jca.5046
158
KY Ng, S Chai, M Tong, XY Guan, CH Lin, YP Ching, D Xie, AS Cheng, S Ma. C-terminal truncated hepatitis B virus X protein promotes hepatocellular carcinogenesis through induction of cancer and stem cell-like properties. Oncotarget 2016; 7(17): 24005–24017 https://doi.org/10.18632/oncotarget.8209
159
GJ Weiner. Building better monoclonal antibody-based therapeutics. Nat Rev Cancer 2015; 15(6): 361–370 https://doi.org/10.1038/nrc3930
160
YF Sun, Y Xu, XR Yang, W Guo, X Zhang, SJ Qiu, RY Shi, B Hu, J Zhou, J Fan. Circulating stem cell-like epithelial cell adhesion molecule-positive tumor cells indicate poor prognosis of hepatocellular carcinoma after curative resection. Hepatology 2013; 57(4): 1458–1468 https://doi.org/10.1002/hep.26151
161
P Zhang, B Shi, H Gao, H Jiang, J Kong, J Yan, X Pan, K Li, P Zhang, M Yao, S Yang, J Gu, H Wang, Z Li. An EpCAM/CD3 bispecific antibody efficiently eliminates hepatocellular carcinoma cells with limited galectin-1 expression. Cancer Immunol Immunother 2014; 63(2): 121–132 https://doi.org/10.1007/s00262-013-1497-4
162
J Huang, C Li, Y Wang, H Lv, Y Guo, H Dai, MS Wicha, AE Chang, Q Li. Cytokine-induced killer (CIK) cells bound with anti-CD3/anti-CD133 bispecific antibodies target CD133(high) cancer stem cells in vitro and in vivo. Clin Immunol 2013; 149(1): 156–168 https://doi.org/10.1016/j.clim.2013.07.006
163
Z Xiao, H Chung, B Banan, PT Manning, KC Ott, S Lin, BJ Capoccia, V Subramanian, RR Hiebsch, GA Upadhya, T Mohanakumar, WA Frazier, Y Lin, WC Chapman. Antibody mediated therapy targeting CD47 inhibits tumor progression of hepatocellular carcinoma. Cancer Lett 2015; 360(2): 302–309 https://doi.org/10.1016/j.canlet.2015.02.036
164
L Wang, W Su, Z Liu, M Zhou, S Chen, Y Chen, D Lu, Y Liu, Y Fan, Y Zheng, Z Han, D Kong, JC Wu, R Xiang, Z Li. CD44 antibody-targeted liposomal nanoparticles for molecular imaging and therapy of hepatocellular carcinoma. Biomaterials 2012; 33(20): 5107–5114 https://doi.org/10.1016/j.biomaterials.2012.03.067
165
F Sun, T Wang, J Jiang, Y Wang, Z Ma, Z Li, Y Han, M Pan, J Cai, M Wang, J Zhang. Engineering a high-affinity humanized anti-CD24 antibody to target hepatocellular carcinoma by a novel CDR grafting design. Oncotarget 2017; 8(31): 51238–51252 https://doi.org/10.18632/oncotarget.17228
166
Y Hirohashi, T Torigoe, S Inoda, A Takahashi, R Morita, S Nishizawa, Y Tamura, H Suzuki, M Toyota, N Sato. Immune response against tumor antigens expressed on human cancer stem-like cells/tumor-initiating cells. Immunotherapy 2010; 2(2): 201–211 https://doi.org/10.2217/imt.10.10
167
H Saijo, Y Hirohashi, T Torigoe, V Kochin, H Takahashi, N Sato. Cytotoxic T lymphocytes: the future of cancer stem cell eradication?. Immunotherapy 2013; 5(6): 549–551 https://doi.org/10.2217/imt.13.44
168
Z Deng, Y Wu, W Ma, S Zhang, YQ Zhang. Adoptive T-cell therapy of prostate cancer targeting the cancer stem cell antigen EpCAM. BMC Immunol 2015; 16(1): 1 https://doi.org/10.1186/s12865-014-0064-x
169
RY Alhabbab. Targeting cancer stem cells by genetically engineered chimeric antigen receptor T cells. Front Genet 2020; 11: 312 https://doi.org/10.3389/fgene.2020.00312
170
Y Wang, M Chen, Z Wu, C Tong, H Dai, Y Guo, Y Liu, J Huang, H Lv, C Luo, KC Feng, QM Yang, XL Li, W Han. CD133-directed CAR T cells for advanced metastasis malignancies: a phase I trial. OncoImmunology 2018; 7(7): e1440169 https://doi.org/10.1080/2162402X.2018.1440169
171
H Dai, C Tong, D Shi, M Chen, Y Guo, D Chen, X Han, H Wang, Y Wang, P Shen. Efficacy and biomarker analysis of CD133-directed CAR T cells in advanced hepatocellular carcinoma: a single-arm, open-label, phase II trial. OncoImmunology 2020; 9(1): 1846926 https://doi.org/10.1080/2162402X.2020.1846926
172
Y Zhai, K He, L Huang, X Shang, G Wang, G Yuan, ZG Han. DLK1-directed chimeric antigen receptor T-cell therapy for hepatocellular carcinoma. Liver Int 2022; 42(11): 2524–2537 https://doi.org/10.1111/liv.15411
173
M Dal Bo, E De Mattia, L Baboci, S Mezzalira, E Cecchin, YG Assaraf, G Toffoli. New insights into the pharmacological, immunological, and CAR-T-cell approaches in the treatment of hepatocellular carcinoma. Drug Resist Updat 2020; 51: 100702 https://doi.org/10.1016/j.drup.2020.100702
174
RA Morgan, JC Yang, M Kitano, ME Dudley, CM Laurencot, SA Rosenberg. Case report of a serious adverse event following the administration of T cells transduced with a chimeric antigen receptor recognizing ERBB2. Mol Ther 2010; 18(4): 843–851 https://doi.org/10.1038/mt.2010.24
175
S Sun, H Hao, G Yang, Y Zhang, Y Fu. Immunotherapy with CAR-modified T cells: toxicities and overcoming strategies. J Immunol Res 2018; 2018: 2386187 https://doi.org/10.1155/2018/2386187
176
YJ Choi, SJ Park, YS Park, HS Park, KM Yang, K Heo. EpCAM peptide-primed dendritic cell vaccination confers significant anti-tumor immunity in hepatocellular carcinoma cells. PLoS One 2018; 13(1): e0190638 https://doi.org/10.1371/journal.pone.0190638
177
JC Sun, K Pan, MS Chen, QJ Wang, H Wang, HQ Ma, YQ Li, XT Liang, JJ Li, JJ Zhao, YB Chen, XH Pang, WL Liu, Y Cao, XY Guan, QZ Lian, JC Xia. Dendritic cells-mediated CTLs targeting hepatocellular carcinoma stem cells. Cancer Biol Ther 2010; 10(4): 368–375 https://doi.org/10.4161/cbt.10.4.12440
178
QZ Pan, K Pan, QJ Wang, DS Weng, JJ Zhao, HX Zheng, XF Zhang, SS Jiang, L Lv, Y Tang, YQ Li, J He, Q Liu, CL Chen, HX Zhang, JC Xia. Annexin A3 as a potential target for immunotherapy of liver cancer stem-like cells. Stem Cells 2015; 33(2): 354–366 https://doi.org/10.1002/stem.1850
179
Y Wang, Q Zhao, B Zhao, Y Zheng, Q Zhuang, N Liao, P Wang, Z Cai, D Zhang, Y Zeng, X Liu. Remodeling tumor-associated neutrophils to enhance dendritic cell-based HCC neoantigen nano-vaccine efficiency. Adv Sci (Weinh) 2022; 9(11): e2105631 https://doi.org/10.1002/advs.202105631
