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中华介入放射学电子杂志 ›› 2021, Vol. 09 ›› Issue (02) : 204 -209. doi: 10.3877/cma.j.issn.2095-5782.2021.02.016

所属专题: 文献

综述

肝癌免疫治疗联合放射治疗进展
刘佳妮1, 徐西伟2, 邓云2, 陈少亿2, 张可3,()   
  1. 1. 519000 广东珠海,中山大学附属第五医院广东省生物医学影像重点实验室;519000 广东珠海,中山大学附属第五医院肿瘤中心
    2. 519000 广东珠海,中山大学附属第五医院肿瘤中心
    3. 519000 广东珠海,中山大学附属第五医院广东省生物医学影像重点实验室;519000 广东珠海,中山大学附属第五医院介入医学中心
  • 收稿日期:2020-12-02 出版日期:2021-05-25
  • 通信作者: 张可
  • 基金资助:
    中国博士后科学基金(2019M663274)

Advances in immunotherapy combined with radiotherapy for hepatocellular carcinoma

Jiani Liu1, Xiwei Xu2, Yun Deng2, Shaoyi Chen2, Ke Zhang3,()   

  1. 1. Guangdong Provincial Key Laboratory of Biomedical Imaging, the Fifth Affiliated Hospital of Sun Yat-sen University, Guangdong Zhuhai 519000, China; Cancer Center, the Fifth Affiliated Hospital of Sun Yat-sen University, Guangdong Zhuhai 519000, China
    2. Cancer Center, the Fifth Affiliated Hospital of Sun Yat-sen University, Guangdong Zhuhai 519000, China
    3. Guangdong Provincial Key Laboratory of Biomedical Imaging, the Fifth Affiliated Hospital of Sun Yat-sen University, Guangdong Zhuhai 519000, China; Interventional Medical Center, the Fifth Affiliated Hospital of Sun Yat-sen University, Guangdong Zhuhai 519000, China
  • Received:2020-12-02 Published:2021-05-25
  • Corresponding author: Ke Zhang
引用本文:

刘佳妮, 徐西伟, 邓云, 陈少亿, 张可. 肝癌免疫治疗联合放射治疗进展[J/OL]. 中华介入放射学电子杂志, 2021, 09(02): 204-209.

Jiani Liu, Xiwei Xu, Yun Deng, Shaoyi Chen, Ke Zhang. Advances in immunotherapy combined with radiotherapy for hepatocellular carcinoma[J/OL]. Chinese Journal of Interventional Radiology(Electronic Edition), 2021, 09(02): 204-209.

免疫检查点抑制剂(ICI)的应用给肝细胞癌(HCC)的全身性治疗带来了新的选择。肿瘤的治疗经历了从传统治疗模式向靶向肿瘤微环境(TME)模式的巨大转变。然而,单独使用免疫检查点阻断(ICB)药物治疗的疗效有限,而将免疫疗法与当前的治疗策略相结合可能产生更好的效果。放射治疗(RT)是包括HCC在内的实体癌症治疗中不可或缺的组成部分。体部立体定向放射治疗(SBRT)在过去的10年中已被用于治疗原发性HCC并且取得了不错的成绩。大剂量的放疗更容易产生远位效应,提示其潜在的免疫激活作用。免疫治疗与放射治疗相结合可能是一种有希望协同增强疗效的策略。其机制可能是射线照射到肿瘤部位会同时影响肿瘤细胞和周围的基质细胞。辐射诱导的癌细胞损伤暴露了肿瘤特异性抗原,使其在免疫监视中可见,并促进细胞毒性T细胞的启动和激活。RT和ICB联合治疗疗效在一些临床研究中也得到了证实。但是要最大程度地发挥两者联用的疗效是有待解决的挑战。文章总结了HCC中RT和ICB联合治疗的进展,以及放疗和免疫系统协同作用的机制,并讨论了目前放疗和免疫检查点阻断疗法中的挑战以及未来增强这种组合可能的方法。

The application of immune checkpoint inhibitors (ICB) has led to significant advances in systemic therapy for advanced hepatocellular carcinoma (HCC). The systemic treatment of cancer has experienced tremendous paradigm towards targeting tumor microenvironment (TME). However, the efficacy of ICB therapy alone is limited, and combining immunotherapy with current treatment strategies may yield better results. Radiotherapy (RT) is an integral part of solid cancer therapy including HCC. Stereotactic body radiotherapy (SBRT) has been used to treat primary HCC for the past ten years and has achieved good results. High dose radiotherapy is more likely to produce abscopal effects, suggesting its potential role in immune activation. The combination of immunotherapy and radiotherapy may be a promising strategy for synergistically enhancing efficacy. Radiation induced cancer cell damage exposes tumor-specific antigens that are visible under immune surveillance and promotes the initiation and activation of cytotoxic T cells. Radiation induced tumor microenvironmental regulation may also promote the recruitment and infiltration of immune cells. The efficacy of RT combined with ICB has also been demonstrated in some clinical studies. But there are still unsolved challenges to make the most appropriate combination strategy. Here, we summarize the advances in combination therapy of RT and ICB in HCC, the mechanisms by which radiotherapy and the immune system work together, and discuss the challenges of current radiotherapy and immune checkpoint blocking therapies and possible strategies to enhance this combination in the future.

[1]
Ghouri YA, Mian I, Rowe JH. Review of hepatocellular carcinoma: epidemiology, etiology, and carcinogenesis[J]. J Carcinog, 2017, 23(6): 1388-1396.
[2]
Muz B, de la Puente P, Azab F, et al. The role of hypoxia in cancer progression, angiogenesis, metastasis, and resistance to therapy[J]. Hypoxia (Auckl), 2015, 3: 83-92.
[3]
Albillos A, Lario M, Alvarez-Mon M. Cirrhosis-associated immune dysfunction: distinctive features and clinical relevance[J]. J Hepatol, 2014, 61(6): 1385-1396.
[4]
Vogel A, Cervantes A, Chau I, et al. Hepatocellular carcinoma: ESMO clinical practice guidelines for diagnosis, treatment and follow-up[J]. Ann Oncol, 2018, 29(Suppl 4): iv238-255.
[5]
Sangro B, Park JW, Cruz CMD, et al. A randomized, multicenter, phase 3 study of nivolumab vs sorafenib as first-line treatment in patients (pts) with advanced hepatocellular carcinoma (HCC): CheckMate-459[J]. J Clin Oncol, 2016, 34(15_suppl): TPS4147-TPS4147.
[6]
Yau T, Kang YK, Kim TY, et al. Nivolumab (NIVO) + ipilimumab (IPI) combination therapy in patients(pts) with advanced hepatocellular carcinoma (aHCC): results from CheckMate 040[J]. J Clin Oncol, 2019, 37(15_suppl): 4012.
[7]
Deng L, Liang H, Burnette B, et al. Irradiation and anti-PD-L1 treatment synergistically promote antitumor immunity in mice[J]. J Clin Invest, 2014, 124(2): 687-695.
[8]
Zhu AX, Duda DG, Sahani DV, et al. HCC and angiogenesis: possible targets and future directions[J]. Nat Rev Clin Oncol, 2011, 8(5): 292-301.
[9]
Chen J, Zaidi S, Rao S, et al. Analysis of genomes and transcriptomes of hepatocellular carcinomas identifies mutations and gene expression changes in the transforming growth factor-β pathway[J]. Gastroenterology, 2018, 154(1): 195-210.
[10]
Noy R, Pollard JW. Tumor-associated macrophages: from mechanisms to therapy[J]. Immunity, 2014, 41(1): 49-61.
[11]
Zheng C, Zheng L, Yoo JK, et al. Landscape of infiltrating t cells in liver cancer revealed by single-cell sequencing[J]. Cell, 2017, 169(7): 1342-1356.
[12]
Zhang JP, Yan J, Xu J, et al. Increased intratumoral IL-17-producing cells correlate with poor survival in hepatocellular carcinoma patients[J]. J Hepatol, 2009, 50(5): 980-989.
[13]
LaCasse CJ, Janikashvili N, Larmonier CB, et al. Th-1 lymphocytes induce dendritic cell tumor killing activity by an IFN-gamma-dependent mechanism[J]. J Immunol, 2011, 187(12): 6310-6317.
[14]
Lee HL, Jang JW, Lee SW, et al. Inflammatory cytokines and change of Th1/Th2 balance as prognostic indicators for hepatocellular carcinoma in patients treated with transarterial chemoembolization[J]. Sci Rep, 2019, 9(1): 3260.
[15]
DeNardo DG, Barreto JB, Andreu P, et al. CD4(+) T cells regulate pulmonary metastasis of mammary carcinomas by enhancing protumor properties of macrophages[J]. Cancer Cell, 2009, 16(2): 91-102.
[16]
Cai L, Zhang Z, Zhou L, et al. Functional impairment in circulating and intrahepatic NK cells and relative mechanism in hepatocellular carcinoma patients[J]. Clin Immunol, 2008, 129(3): 428-437.
[17]
Barber DL, Wherry EJ, Masopust D, et al. Restoring function in exhausted CD8 T cells during chronic viral infection[J]. Nature, 2006, 439(7077): 682-687.
[18]
Greten TF, Sangro B. Targets for immunotherapy of liver cancer[J]. J Hepatol, 2017, 68(1): 157-166.
[19]
Huppert LA, Gordan JD, Kelley RK. Checkpoint inhibitors for the treatment of advanced hepatocellular carcinoma[J]. Clin Liver Dis (Hoboken), 2020, 15(2): 53-58.
[20]
Twyman-Saint Victor C, Rech AJ, Maity A, et al. Radiation and dual checkpoint blockade activate non-redundant immune mechanisms in cancer[J]. Nature, 2015, 520(7547): 373-377.
[21]
Egen JG, Kuhns MS, Allison JP. CTLA-4: new insights into its biological function and use in tumor immunotherapy[J]. Nat Immunol, 2002, 3(7): 611-618.
[22]
Lim CJ, Chew V. Impact of viral etiologies on the development of novel immunotherapy for hepatocellular carcinoma[J]. Semin Liver Dis, 2020, 40 (2): 131-142.
[23]
Ohri N, Dawson LA, Krishnan S, et al. Radiotherapy for hepatocellular carcinoma: new indications and directions for future study[J]. J Natl Cancer Inst, 2016, 108(9): djw133.
[24]
Bujold A, Massey CA, Kim JJ, et al. Sequential phase I and II trials of stereotactic body radiotherapy for locally advanced hepatocellular carcinoma[J]. J Clin Oncol, 2013, 31(13): 1631-1639.
[25]
Mazzaferro V, Sposito C, Bhoori S, et al. Yttrium-90 radioembolization for intermediate-advanced hepatocellular carcinoma: a phase 2 study[J]. Hepatology, 2013, 57(5): 1826-1837.
[26]
Sauter B, Albert ML, Francisco L, et al. Consequences of cell death: exposure to necrotic tumor cells, but not primary tissue cells or apoptotic cells, induces the maturation of immunostimulatory dendritic cells[J]. J ExpMed, 2000, 191(3): 423-434.
[27]
Deng L, Liang H, Xu M, et al. STING dependent cytosolic DNA sensing promotes radiation-induced type I interferon-dependent antitumor immunity in immunogenic tumors[J]. Immunity, 2014, 41(5): 843-852.
[28]
Jacquelot N, Yamazaki T, Roberti MP, et al. Sustained type I interferon signaling as a mechanism of resistance to PD-1 blockade[J]. Cell Res, 2019, 29(10): 846-861.
[29]
Dovedi SJ, Adlard AL, Lipowska-Bhalla G, et al. Acquired resistance to fractionated radiotherapy can be overcome by concurrent PD-L1 blockade[J]. Cancer Res, 2014, 74(19): 5458-5468.
[30]
Vermeer, DW, Spanos, WC, Vermeer, PD, et al. Radiation-induced loss of cell surface CD47 enhances immunemediated clearance of human papillomavirus-positive cancer[J]. Int J Cancer, 2013, 133: 120-129.
[31]
Yoshimoto Y, Oike T, Okonogi N, et al. Carbon-ion beams induce production of an immune mediator protein, high mobility group box 1, at levels comparable with X-ray irradiation[J]. J Radiat Res, 2015, 56: 509-514.
[32]
shikawa H, Ma Z, Barber GN. STING regulates intracellular DNA mediated, type I interferon-dependent innate immunity[J]. Nature, 2009, 461: 788-792.
[33]
Dovedi SJ, Adlard AL, Lipowska-Bhalla G, et al. Acquired resistance to fractionated radiotherapy can be overcome by concurrent PD-L1 blockade[J]. Cancer Res, 2014, 74(19): 5458-5468.
[34]
Chiang CL, Chan ACY, Chiu KWH, et al. Combined stereotactic body radiotherapy and checkpoint inhibition in unresectable hepatocellular carcinoma: a potential synergistic treatment strategy[J]. Front Oncol, 2019, 9: 1157.
[35]
Tang C, Welsh JW, de Groot P, et al. Ipilimumab with stereotactic ablative radiation therapy: phase I results and immunologic correlates from peripheral T cells[J]. Clin Cancer Res, 2017, 23(6): 1388-1396.
[36]
Buchwald ZS, Wynne J, Nasti TH, et al. Radiation, immune checkpoint blockade and the abscopal effect: a critical review on timing, dose and fractionation[J]. Front Oncol, 2018, 8: 612.
[37]
Bonta I, Isac JF, Meiri E, et al. Correlation between tumor mutation burden and response to immunotherapy[J]. J Clin Oncol, 2017, 35 (15_suppl): e14579.
[38]
Wu JB, Tang YL, Liang XH. Targeting VEGF pathway to normalize the vasculature: an emerging insight in cancer therapy[J]. Oncol Targets Ther, 2018, 11: 6901-6909.
[39]
Asghar K, Farooq A, Zulfiqar B, et al. Indoleamine 2,3-dioxygenase: as a potential prognostic marker and immunotherapeutic target for hepatocellular carcinoma[J]. World J Gastroenterol, 2017, 23(13): 2286-2293.
[40]
Liu M, Li Z, Yao W, et al. IDO inhibitor synergized with radiotherapy to delay tumor growth by reversing T cell exhaustion[J]. Mol Med Rep, 2020, 21(1): 445-453.
[41]
Zheng Y, Liao N, Wu Y, et al. High expression of B7-H2 or B7-H3 is associated with poor prognosis in hepatocellular carcinoma[J]. Mol Med Rep, 2019, 19(5): 4315-4325.
[42]
Ma S, Li X, Wang X, et al. Current progress in CAR-T cell therapy for solid tumors[J]. Int J Biol Sci, 2019, 15(12): 2548-2560.
[43]
Kaseb AO, Hassan M, Lacin S, et al. Evaluating clinical and prognostic implications of Glypican-3 in hepatocellular carcinoma[J]. Oncotarget, 2016, 7(43): 69916-69926.
[44]
Shi D, Shi Y, Kaseb AO, et al. Chimeric antigen receptor-glypican-3 t-cell therapy for advanced hepatocellular carcinoma: results of phase 1 trials[J]. Clin Cancer Res, 2020, 26(15): 3979-3989.
[45]
Forker LJ, Choudhury A, Kiltie AE. Biomarkers of tumour radiosensitivity and predicting benefit from radiotherapy[J]. Clin Oncol (R Coll Radiol), 2015, 27(10): 561-569.
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