肝癌中SWI/SNF复合物突变与免疫检查点抑制剂治疗应答反应的研究进展

doi:10.3969/j.issn.1006-7795.2023.05.010

摘要/Abstract

摘要： WI/SNF（SWItch/sucrose non-fermentable）复合物是一类依赖ATP的染色质重塑复合物，其亚基在肝癌中频繁发生突变或缺失。这些突变或缺失易导致染色质结构和功能异常，进而影响肝癌细胞的生物学行为，并影响肝癌患者对免疫检查点抑制剂治疗的应答反应。本文主要总结了肝癌中SWI/SNF复合物亚基突变与免疫检查点抑制剂治疗应答反应的研究进展，探讨其亚基突变与免疫检查点抑制剂治疗应答率、耐药性和预测标志物的关系，并展望未来的研究方向和临床应用前景。

关键词: SWI/SNF复合物, 肝癌, 免疫检查点抑制剂, 染色质重塑

Abstract: The SWI/SNF (SWItch/sucrose non-fermentable) complex is an ATP-dependent chromatin remodeling complex, and its subunits are frequently mutated or lost in hepatocellular carcinoma (HCC). These mutations or losses can lead to abnormal chromatin structure and function, thus affecting the biological behavior of HCC cells and influencing the response to immune checkpoint inhibitors（ICIs）therapy in HCC patients. This review primarily summarizes the research progresses on the subunit mutations of the SWI/SNF complex in HCC and their association with ICIs therapy response. It explores the relationship between subunit mutations, ICIs therapy response rate, drug resistance, and predictive biomarkers, as well as provides insights into future research directions and the clinical application prospects.

Key words: SWI/SNF complex, hepatocellular carcinoma（HCC）, immune checkpoint inhibitors, chromatin remodeling

中图分类号:

R735.7

尹雪, 于明航, 王玺, 陈京龙. 肝癌中SWI/SNF复合物突变与免疫检查点抑制剂治疗应答反应的研究进展[J]. 首都医科大学学报, 2023, 44(5): 768-774.

Yin Xue, Yu Minghang, Wang Xi, Chen Jinglong. Progresses on the mutation of SWI/SNF complex and its impact on immune checkpoint inhibitor therapy response in hepatocellular carcinoma[J]. Journal of Capital Medical University, 2023, 44(5): 768-774.

参考文献

［1］Bray F, Ferlay J, Soerjomataram I, et al. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries［J］. CA Cancer J Clin, 2018, 68(6): 394-424.
［2］Siegel R L, Miller K D, Wagle N S, et al. Cancer statistics, 2023［J］. CA Cancer J Clin, 2023, 73(1): 17-48.
［3］Yang J D, Hainaut P, Gores G J, et al. A global view of hepatocellular carcinoma: trends, risk, prevention and management［J］. Nat Rev Gastroenterol Hepatol, 2019, 16(10): 589-604.
［4］Yang C, Zhang H L, Zhang L M, et al. Evolving therapeutic landscape of advanced hepatocellular carcinoma［J］. Nat Rev Gastroenterol Hepatol, 2023, 20(4): 203-222.
［5］Forner A, Reig M, Bruix J. Hepatocellular carcinoma［J］. Lancet, 2018, 391(10127): 1301-1314.
［6］El-Khoueiry A B, Sangro B, Yau T, et al. Nivolumab in patients with advanced hepatocellular carcinoma (CheckMate 040): an open-label, non-comparative, phase 1/2 dose escalation and expansion trial［J］. Lancet, 2017, 389(10088): 2492-2502.
［7］FINN R S, QIN S K, IKEDA M, et al. IMbrave150: updated overall survival (OS) data from a global, randomized, open-label phase Ⅲ study of atezolizumab (atezo)+ bevacizumab (bev) versus sorafenib (sor) in patients (pts) with unresectable hepatocellular carcinoma (HCC)［J］. J Clin Oncol, 2021, 39(3_suppl): 267.
［8］Llovet J M, Castet F, Heikenwalder M, et al. Immunotherapies for hepatocellular carcinoma［J］. Nat Rev Clin Oncol, 2022, 19(3): 151-172.
［9］Sangro B, Sarobe P, Hervás-Stubbs S, et al. Advances in immunotherapy for hepatocellular carcinoma［J］. Nat Rev Gastroenterol Hepatol, 2021, 18(8): 525-543.
［10］Zhu A X, Finn R S, Edeline J L N, et al. Pembrolizumab in patients with advanced hepatocellular carcinoma previously treated with sorafenib (KEYNOTE-224): a non-randomised, open-label phase 2 trial［J］. Lancet Oncol, 2018, 19(7): 940-952.
［11］Kassabov S R, Zhang B, Persinger J, et al. SWI/SNF unwraps, slides, and rewraps the nucleosome［J］. Mol Cell, 2003, 11(2): 391-403.
［12］Mittal P, Roberts C W M. The SWI/SNF complex in cancer-biology, biomarkers and therapy［J］. Nat Rev Clin Oncol, 2020, 17(7): 435-448.
［13］Centore R C, Sandoval G J, Soares L M M, et al. Mammalian SWI/SNF chromatin remodeling complexes: emerging mechanisms and therapeutic strategies［J］. Trends Genet, 2020, 36(12): 936-950.
［14］Helming K C, Wang X F, Roberts C W M. Vulnerabilities of mutant SWI/SNF complexes in cancer［J］. Cancer Cell, 2014, 26(3): 309-317.
［15］Kadoch C, Crabtree G R. Mammalian SWI/SNF chromatin remodeling complexes and cancer: mechanistic insights gained from human genomics［J］. Sci Adv, 2015, 1(5): e1500447.
［16］Clapier C R, Iwasa J, Cairns B R, et al. Mechanisms of action and regulation of ATP-dependent chromatin-remodelling complexes［J］. Nat Rev Mol Cell Biol, 2017, 18(7): 407-422.
［17］Ho L, Ronan J L, Wu J, et al. An embryonic stem cell chromatin remodeling complex, esBAF, is essential for embryonic stem cell self-renewal and pluripotency［J］. Proc Natl Acad Sci U S A, 2009, 106(13): 5181-5186.
［18］Bayona-Feliu A, Barroso S, Muoz S, et al. The SWI/SNF chromatin remodeling complex helps resolve R-loop-mediated transcription-replication conflicts［J］. Nat Genet, 2021, 53(7): 1050-1063.
［19］Mashtalir N, DAvino A R, Michel B C, et al. Modular organization and assembly of SWI/SNF family chromatin remodeling complexes［J］. Cell, 2018, 175(5): 1272-1288.e20.
［20］Wang X F, Wang S, Troisi E C, et al. BRD9 defines a SWI/SNF sub-complex and constitutes a specific vulnerability in malignant rhabdoid tumors［J］. Nat Commun, 2019, 10(1): 1881.
［21］Hu B, Lin J Z, Yang X B, et al. The roles of mutated SWI/SNF complexes in the initiation and development of hepatocellular carcinoma and its regulatory effect on the immune system: a review［J］. Cell Prolif, 2020, 53(4): e12791.
［22］Alver B H, Kim K H, Lu P, et al. The SWI/SNF chromatin remodelling complex is required for maintenance of lineage specific enhancers［J］. Nat Commun, 2017, 8: 14648.
［23］Hodges H C, Stanton B Z, Cermakova K, et al. Dominant-negative SMARCA4 mutants alter the accessibility landscape of tissue-unrestricted enhancers［J］. Nat Struct Mol Biol, 2018, 25(1): 61-72.
［24］Tolstorukov M Y, Sansam C G, Lu P, et al. Swi/Snf chromatin remodeling/tumor suppressor complex establishes nucleosome occupancy at target promoters［J］. Proc Natl Acad Sci U S A, 2013, 110(25): 10165-10170.
［25］Barisic D, Stadler M B, Iurlaro M, et al. Mammalian ISWI and SWI/SNF selectively mediate binding of distinct transcription factors［J］. Nature, 2019, 569(7754): 136-140.
［26］Battistello E, Hixon K A, Comstock D E, et al. Stepwise activities of mSWI/SNF family chromatin remodeling complexes direct T cell activation and exhaustion［J］. Mol Cell, 2023, 83(8): 1216-1236.e12.
［27］Drosos Y, Myers J A, Xu B S, et al. NSD1 mediates antagonism between SWI/SNF and polycomb complexes and is required for transcriptional activation upon EZH2 inhibition［J］. Mol Cell, 2022, 82(13): 2472-2489.e8.
［28］Xiao L B, Parolia A, Qiao Y Y, et al. Targeting SWI/SNF ATPases in enhancer-addicted prostate cancer［J］. Nature, 2022, 601(7893): 434-439.
［29］Yao X S, Hong J H, Nargund A M, et al. PBRM1-deficient PBAF complexes target aberrant genomic loci to activate the NF-κB pathway in clear cell renal cell carcinoma［J］. Nat Cell Biol, 2023, 25(5): 765-777.
［30］Loesch R, Chenane L D, Colnot S. ARID2 chromatin remodeler in hepatocellular carcinoma［J］. Cells, 2020, 9(10): 2152.
［31］Yim S Y, Kang S H, Shin J H, et al. Low ARID1A expression is associated with poor prognosis in hepatocellular carcinoma［J］. Cells, 2020, 9(9): 2002.
［32］Zhang F K, Ni Q Z, Wang K, et al. Targeting USP9X-AMPK axis in ARID1A-deficient hepatocellular carcinoma［J］. Cell Mol Gastroenterol Hepatol, 2022, 14(1): 101-127.
［33］Mullen J, Kato S, Sicklick J K, et al. Targeting ARID1A mutations in cancer［J］. Cancer Treat Rev, 2021, 100: 102287.
［34］Zhang S S, Zhou Y F, Cao J, et al. mTORC1 promotes ARID1A degradation and oncogenic chromatin remodeling in hepatocellular carcinoma［J］. Cancer Res, 2021, 81(22): 5652-5665.
［35］Shen J F, Ju Z L, Zhao W, et al. ARID1A deficiency promotes mutability and potentiates therapeutic antitumor immunity unleashed by immune checkpoint blockade［J］. Nat Med, 2018, 24(5): 556-562.
［36］Wilson B G, Roberts C W M. SWI/SNF nucleosome remodellers and cancer［J］. Nat Rev Cancer, 2011, 11(7): 481-492.
［37］Wu J N, Roberts C W M. ARID1A mutations in cancer: another epigenetic tumor suppressor?［J］. Cancer Discov, 2013, 3(1): 35-43.
［38］Mandal J, Mandal P, Wang T L, et al. Treating ARID1A mutated cancers by harnessing synthetic lethality and DNA damage response［J］. J Biomed Sci, 2022, 29(1): 71.
［39］He F, Li J, Xu J F, et al. Decreased expression of ARID1A associates with poor prognosis and promotes metastases of hepatocellular carcinoma［J］. J Exp Clin Cancer Res, 2015, 34(1): 47.
［40］Hu C B, Li W P, Tian F, et al. ARID1A regulates response to anti-angiogenic therapy in advanced hepatocellular carcinoma［J］. J Hepatol, 2018, 68(3): 465-475.
［41］Cheng S, Wang L, Deng C H, et al. ARID1A represses hepatocellular carcinoma cell proliferation and migration through lncRNA MVIH［J］. Biochem Biophys Res Commun, 2017, 491(1): 178-182.
［42］Xiao Y, Liu G D, Ouyang X W, et al. Loss of ARID1A promotes hepatocellular carcinoma progression via up-regulation of MYC transcription［J］. J Clin Transl Hepatol, 2021, 9(4): 528-536.
［43］Sun X X, Wang S C, Wei Y L, et al. Arid1a has Context-dependent oncogenic and tumor suppressor functions in liver cancer［J］. Cancer Cell, 2017, 32(5): 574-589.e6.
［44］Meng G X, Yang C C, Yan L J, et al. The somatic mutational landscape and role of the ARID1A gene in hepatocellular carcinoma［J］. Heliyon, 2023, 9(3): e14307.
［45］Jiang H, Cao H J, Ma N, et al. Chromatin remodeling factor ARID2 suppresses hepatocellular carcinoma metastasis via DNMT1-snail axis［J］. Proc Natl Acad Sci U S A, 2020, 117(9): 4770-4780.
［46］Oba A, Shimada S, Akiyama Y, et al. ARID2 modulates DNA damage response in human hepatocellular carcinoma cells［J］. J Hepatol, 2017, 66(5): 942-951.
［47］Duan Y J, Tian L, Gao Q Z, et al. Chromatin remodeling gene ARID2 targets cyclin D1 and cyclin E1 to suppress hepatoma cell progression［J］. Oncotarget, 2016, 7(29): 45863-45875.
［48］Cao H J, Jiang H, Ding K, et al. ARID2 mitigates hepatic steatosis via promoting the ubiquitination of JAK2［J］. Cell Death Differ, 2023, 30(2): 383-396.
［49］Hargreaves D C, Crabtree G R. ATP-dependent chromatin remodeling: genetics, genomics and mechanisms［J］. Cell Res, 2011, 21(3): 396-420.
［50］Concepcion C P, Ma S, Lafave L M, et al. Smarca4 inactivation promotes lineage-specific transformation and early metastatic features in the lung［J］. Cancer Discov, 2022, 12(2): 562-585.
［51］Neil A J, Zhao L, Isidro R A, et al. SMARCA4 mutations in carcinomas of the esophagus, esophagogastric junction, and stomach［J］. Mod Pathol, 2023, 36(6): 100183.
［52］Romero O A, Vilarrubi A, Alburquerque-Bejar J J, et al. SMARCA4 deficient tumours are vulnerable to KDM6A/UTX and KDM6B/JMJD3 blockade［J］. Nat Commun, 2021, 12(1): 4319.
［53］Tian Y M, Xu L, Li X, et al. SMARCA4: current status and future perspectives in non-small-cell lung cancer［J］. Cancer Lett, 2023, 554: 216022.
［54］Wang P, Song X H, Cao D, et al. Oncogene-dependent function of BRG1 in hepatocarcinogenesis［J］. Cell Death Dis, 2020, 11(2): 91.
［55］Kim S Y, Shen Q Y, Son K, et al. SMARCA4 oncogenic potential via IRAK1 enhancer to activate Gankyrin and AKR1B10 in liver cancer［J］. Oncogene, 2021, 40(28): 4652-4662.
［56］Wang D, Wang J C, Zhou D M, et al. SWI/SNF complex genomic alterations as a predictive biomarker for response to immune checkpoint inhibitors in multiple cancers［J］. Cancer Immunol Res, 2023, 11(5): 646-656.
［57］Martins F, Sofiya L, Sykiotis G P, et al. Adverse effects of immune-checkpoint inhibitors: epidemiology, management and surveillance［J］. Nat Rev Clin Oncol, 2019, 16(9): 563-580.
［58］Topalian S L, Hodi F S, Brahmer J R, et al. Safety, activity, and immune correlates of anti-PD-1 antibody in cancer［J］. N Engl J Med, 2012, 366(26): 2443-2454.
［59］Goswami S, Chen Y L, Anandhan S, et al. ARID1A mutation plus CXCL13 expression act as combinatorial biomarkers to predict responses to immune checkpoint therapy in mUCC［J］. Sci Transl Med, 2020, 12(548): eabc4220.
［60］Zhou M, Yuan J L, Deng Y Q, et al. Emerging role of SWI/SNF complex deficiency as a target of immune checkpoint blockade in human cancers［J］. Oncogenesis, 2021, 10(1): 3.
［61］Abou Alaiwi S, Nassar A H, Xie W L, et al. Mammalian SWI/SNF complex genomic alterations and immune checkpoint blockade in solid tumors［J］. Cancer Immunol Res, 2020, 8(8): 1075-1084.
［62］Astori A, Tingvall-Gustafsson J, Kuruvilla J, et al. ARID1a associates with lymphoid-restricted transcription factors and has an essential role in T cell development［J］. J Immunol, 2020, 205(5): 1419-1432.
［63］Okamura R, Kato S, Lee S Z A, et al. ARID1A alterations function as a biomarker for longer progression-free survival after anti-PD-1/PD-L1 immunotherapy［J］. J Immunother Cancer, 2020, 8(1): e000438.
［64］Fang J Z, Li C, Liu X Y, et al. Hepatocyte-Specific ARID1A deficiency initiates mouse steatohepatitis and hepatocellular carcinoma ［J］. PLoS One, 2015, 10(11): e0143042.
［65］Kong M, Chen X Y, Xu H H, et al. Hepatocyte-specific deletion of Brg1 alleviates methionine-and-choline-deficient diet (MCD) induced non-alcoholic steatohepatitis in mice［J］. Biochem Biophys Res Commun, 2018, 503(1): 344-351.
［66］Pan D, Kobayashi A, Jiang P, et al. A major chromatin regulator determines resistance of tumor cells to T cell-mediated killing［J］. Science, 2018, 359(6377): 770-775.
［67］Fan Z W, Kong M, Dong W H, et al. Trans-activation of eotaxin-1 by Brg1 contributes to liver regeneration［J］. Cell Death Dis, 2022, 13(5): 495.
［68］Miao D N, Margolis C A, Gao W H, et al. Genomic correlates of response to immune checkpoint therapies in clear cell renal cell carcinoma［J］. Science, 2018, 359(6377): 801-806.