肿瘤浸润淋巴细胞治疗胆道癌研究进展

万雪帅; 谢小兵; 赵海涛; 谷为岳; 张恒辉

doi:10.3969/j.issn.1001-5256.2023.05.005

肿瘤浸润淋巴细胞治疗胆道癌研究进展

DOI: 10.3969/j.issn.1001-5256.2023.05.005

1.
中国医学科学院北京协和医院肝脏外科，北京 100730
2.
卡替医疗技术有限公司，北京 101111
3.
北京臻知医学科技有限公司，免疫细胞治疗北京市工程研究中心，北京 102600

基金项目:

北京协和医院中央高水平医院临床科研专项 (2022-PUMCH-B-128);

中国医学科学院临床与转化医学研究专项“滚动支持项目” (2022-I2M-C & T-A-003);

中国医学科学院医学与健康科技创新工程2021年“揭榜挂帅”项目 (2021-I2M-1-061);

中国医学科学院医学与健康科技创新工程2021年“揭榜挂帅”项目 (2021-I2M-1-003);

希思科-默沙东肿瘤研究基金项目 (Y-MSDZD2021-0213);

希思科-恒瑞肿瘤研究基金项目 (Y-HR2019-0239);

希思科-恒瑞肿瘤研究基金项目 (Y-HR2020MS-0415);

希思科-恒瑞肿瘤研究基金项目 (Y-HR2020QN-0414);

国家高层次人才特殊支持计划(万人计划)

利益冲突声明：本文不存在任何利益冲突。

作者贡献声明：万雪帅、谢小兵负责撰写论文；张恒辉负责修改论文；赵海涛、谷为岳负责指导、审阅论文。

详细信息

通信作者:
赵海涛，zhaoht@pumch.cn (ORCID: 0000-0002-3444-8044)

计量
- 文章访问数: 534
- HTML全文浏览量: 206
- PDF下载量: 113
- 被引次数: 0
出版历程
- 收稿日期: 2023-03-10
- 录用日期: 2023-04-11
- 出版日期: 2023-05-20

Research advances in tumor-infiltrating lymphocytes in treatment of biliary tract cancer

1.
Department of Liver Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Beijing 100730, China
2.
Chineo Therapeutics Co., Ltd., Beijing 101111, China
3.
Beijing Immupeutics Medicine Technology Co., Ltd., Beijing Engineering Research Center of Immunocellular Therapy, Beijing 102600, China

Research funding:

National High Level Hospital Clinical Research Funding (2022-PUMCH-B-128);

CAMS Innovation Fund for Medical Sciences(CIFMS) (2022-I2M-C & T-A-003);

CAMS Innovation Fund for Medical Sciences (CIFMS) (2021-I2M-1-061);

CAMS Innovation Fund for Medical Sciences (CIFMS) (2021-I2M-1-003);

CSCO-MSD Cancer Research Fund (Y-MSDZD2021-0213);

CSCO-Hengrui Cancer Research Fund (Y-HR2019-0239);

CSCO-Hengrui Cancer Research Fund (Y-HR2020MS-0415);

CSCO-Hengrui Cancer Research Fund (Y-HR2020QN-0414);

National Ten-thousand Talent Program

More Information

Corresponding author: ZHAO Haitao, zhaoht@pumch.cn (ORCID: 0000-0002-3444-8044)

摘要

摘要: 肿瘤浸润淋巴细胞(TIL)是存在于肿瘤实质和间质内的以T淋巴细胞为主的一类异质性淋巴细胞群体。将其从肿瘤组织消化和分离出来，经体外培养活化和扩增后，回输到患者体内可以起到杀伤肿瘤细胞的作用。TIL具有T淋巴细胞抗原受体的高度多样性、优异的浸润肿瘤部位能力以及低毒性等优势，被认为有希望用于治疗恶性实体肿瘤。目前，TIL疗法已在多种实体瘤中作为二线治疗进行临床试验并取得初步疗效。虽然目前尚无TIL应用于胆道癌单一病种的临床队列报道，近期的多癌种临床报道提供了少数接受TIL治疗的胆道癌患者的疗效信息，初步证实了安全性和有效性。但由于胆道癌一般被认为是大多数效应T淋巴细胞被隔离在肿瘤边缘的免疫排斥性肿瘤，TIL在胆道癌中的抗肿瘤作用仍难以预测。尝试与不同抗肿瘤方法的联合治疗以及开发新技术修饰细胞以增强TIL抗肿瘤能力是未来可能突破的发展方向。
- 淋巴细胞，肿瘤浸润 /
- 胆道肿瘤 /
- 治疗学
Abstract: Tumor-infiltrating lymphocytes (TILs) are a heterogeneous subset of lymphocytes, mainly T cells, present in tumor parenchyma and stroma. After being digested and isolated from tumor tissue and then cultured in vitro for activation and multiplication, it can be infused back into the patient's body to kill tumor cells. TILs have the advantages of high diversity of TCR, excellent ability to infiltrate into tumor sites, and low toxicity and are considered promising for the treatment of malignant solid tumors. At present, TIL therapy has been tested as a second-line treatment in a variety of solid tumors and has achieved preliminary results. Although there is still no clinical cohort report on the application of TILs in biliary tract cancer (BTC), recent clinical reports on multiple cancers have provided information on the efficacy of TIL therapy in a small number of BTC patients, which preliminarily confirmed the safety and efficacy of TIL therapy. However, since BTC is generally considered an immunologically repulsive tumor in which most effector T cells are sequestered at the tumor edge, the antitumor effect of TILs in BTC remains difficult to predict. Combination therapy with different anti-tumor methods and the development of new techniques to modify cells to enhance the anti-tumor ability of TILs are possible directions for breakthrough in the future.
- Lymphocytes, Tumor-Infiltrating /
- Biliary Tract Neoplasms /
- Therapeutics

HTML全文

参考文献(42)

[1]	SASADA T, SUEKANE S. Variation of tumor-infiltrating lymphocytes in human cancers: controversy on clinical significance[J]. Immunotherapy, 2011, 3(10): 1235-1251. DOI: 10.2217/imt.11.106.
[2]	RASKOV H, ORHAN A, CHRISTENSEN JP, et al. Cytotoxic CD8⁺ T cells in cancer and cancer immunotherapy[J]. Br J Cancer, 2021, 124(2): 359-367. DOI: 10.1038/s41416-020-01048-4.
[3]	WIEDEMANN A, DEPOIL D, FAROUDI M, et al. Cytotoxic T lymphocytes kill multiple targets simultaneously via spatiotemporal uncoupling of lytic and stimulatory synapses[J]. Proc Natl Acad Sci U S A, 2006, 103(29): 10985-10990. DOI: 10.1073/pnas.0600651103.
[4]	ABIKO K, MATSUMURA N, HAMANISHI J, et al. IFN-γ from lymphocytes induces PD-L1 expression and promotes progression of ovarian cancer[J]. Br J Cancer, 2015, 112(9): 1501-1509. DOI: 10.1038/bjc.2015.101.
[5]	AHMADZADEH M, JOHNSON LA, HEEMSKERK B, et al. Tumor antigen-specific CD8 T cells infiltrating the tumor express high levels of PD-1 and are functionally impaired[J]. Blood, 2009, 114(8): 1537-1544. DOI: 10.1182/blood-2008-12-195792.
[6]	INOZUME T, HANADA K, WANG QJ, et al. Selection of CD8⁺PD-1⁺ lymphocytes in fresh human melanomas enriches for tumor-reactive T cells[J]. J Immunother, 2010, 33(9): 956-964. DOI: 10.1097/CJI.0b013e3181fad2b0.
[7]	EBERLEIN TJ, ROSENSTEIN M, ROSENBERG SA. Regression of a disseminated syngeneic solid tumor by systemic transfer of lymphoid cells expanded in interleukin 2[J]. J Exp Med, 1982, 156(2): 385-397. DOI: 10.1084/jem.156.2.385.
[8]	ROSENBERG SA, SPIESS P, LAFRENIERE R. A new approach to the adoptive immunotherapy of cancer with tumor-infiltrating lymphocytes[J]. Science, 1986, 233(4770): 1318-1321. DOI: 10.1126/science.3489291.
[9]	ROSENBERG SA, YANG JC, SHERRY RM, et al. Durable complete responses in heavily pretreated patients with metastatic melanoma using T-cell transfer immunotherapy[J]. Clin Cancer Res, 2011, 17(13): 4550-4557. DOI: 10.1158/1078-0432.CCR-11-0116.
[10]	ROSENBERG SA, PACKARD BS, AEBERSOLD PM, et al. Use of tumor-infiltrating lymphocytes and interleukin-2 in the immunotherapy of patients with metastatic melanoma. A preliminary report[J]. N Engl J Med, 1988, 319(25): 1676-1680. 10.1056/NEJM198812223192527. DOI: 10.1056/NEJM198812223192527
[11]	SHARMA P, HU-LIESKOVAN S, WARGO JA, et al. Primary, adaptive, and acquired resistance to cancer immunotherapy[J]. Cell, 2017, 168(4): 707-723. DOI: 10.1016/j.cell.2017.01.017.
[12]	SIM M, SUN PD. T cell recognition of tumor neoantigens and insights into T cell immunotherapy[J]. Front Immunol, 2022, 13: 833017. DOI: 10.3389/fimmu.2022.833017.
[13]	KRISTENSEN NP, HEEKE C, TVINGSHOLM SA, et al. Neoantigen-reactive CD8⁺ T cells affect clinical outcome of adoptive cell therapy with tumor-infiltrating lymphocytes in melanoma[J]. J Clin Invest, 2022, 132(2): e150535. DOI: 10.1172/JCI150535.
[14]	RATTO GB, ZINO P, MIRABELLI S, et al. A randomized trial of adoptive immunotherapy with tumor-infiltrating lymphocytes and interleukin-2 versus standard therapy in the postoperative treatment of resected nonsmall cell lung carcinoma[J]. Cancer, 1996, 78(2): 244-251. DOI: 10.1002/(SICI)1097-0142(19960715)78:2<244::AID-CNCR9>3.0.CO;2-L.
[15]	XING Y, YASINJAN F, DU Y, et al. Immunotherapy in cervical cancer: From the view of scientometric analysis and clinical trials[J]. Front Immunol, 2023, 14: 1094437. DOI: 10.3389/fimmu.2023.1094437.
[16]	STEVANOVIĆ S, DRAPER LM, LANGHAN MM, et al. Complete regression of metastatic cervical cancer after treatment with human papillomavirus-targeted tumor-infiltrating T cells[J]. J Clin Oncol, 2015, 33(14): 1543-1550. DOI: 10.1200/JCO.2014.58.9093.
[17]	DENG M, RAN P, CHEN L, et al. Proteogenomic characterization of cholangiocarcinoma[J]. Hepatology, 2023, 77(2): 411-429. DOI: 10.1002/hep.32624.
[18]	HYDER O, HATZARAS I, SOTIROPOULOS GC, et al. Recurrence after operative management of intrahepatic cholangiocarcinoma[J]. Surgery, 2013, 153(6): 811-818. DOI: 10.1016/j.surg.2012.12.005.
[19]	ZHOU G, SPRENGERS D, MANCHAM S, et al. Reduction of immunosuppressive tumor microenvironment in cholangiocarcinoma by ex vivo targeting immune checkpoint molecules[J]. J Hepatol, 2019, 71(4): 753-762. DOI: 10.1016/j.jhep.2019.05.026.
[20]	GOEPPERT B, FRAUENSCHUH L, ZUCKNICK M, et al. Prognostic impact of tumour-infiltrating immune cells on biliary tract cancer[J]. Br J Cancer, 2013, 109(10): 2665-2674. DOI: 10.1038/bjc.2013.610.
[21]	LIU D, HEIJ LR, CZIGANY Z, et al. The role of tumor-infiltrating lymphocytes in cholangiocarcinoma[J]. J Exp Clin Cancer Res, 2022, 41(1): 127. DOI: 10.1186/s13046-022-02340-2.
[22]	VIGANO L, SOLDANI C, FRANCESCHINI B, et al. Tumor-infiltrating lymphocytes and macrophages in intrahepatic cholangiocellular carcinoma. Impact on prognosis after complete surgery[J]. J Gastrointest Surg, 2019, 23(11): 2216-2224. DOI: 10.1007/s11605-019-04111-5.
[23]	OSHIKIRI T, MIYAMOTO M, SHICHINOHE T, et al. Prognostic value of intratumoral CD8⁺ T lymphocyte in extrahepatic bile duct carcinoma as essential immune response[J]. J Surg Oncol, 2003, 84(4): 224-228. DOI: 10.1002/jso.10321.
[24]	WOO SR, CORRALES L, GAJEWSKI TF. The STING pathway and the T cell-inflamed tumor microenvironment[J]. Trends Immunol, 2015, 36(4): 250-256. DOI: 10.1016/j.it.2015.02.003.
[25]	KATHER JN, SUAREZ-CARMONA M, CHAROENTONG P, et al. Topography of cancer-associated immune cells in human solid tumors[J]. Elife, 2018, 7: e36967. DOI: 10.7554/eLife.36967.
[26]	ZHOU M, WANG C, LU S, et al. Tumor-associated macrophages in cholangiocarcinoma: complex interplay and potential therapeutic target[J]. EBioMedicine, 2021, 67: 103375. DOI: 10.1016/j.ebiom.2021.103375.
[27]	BRAHMER JR, TYKODI SS, CHOW LQ, et al. Safety and activity of anti-PD-L1 antibody in patients with advanced cancer[J]. N Engl J Med, 2012, 366(26): 2455-2465. DOI: 10.1056/NEJMoa1200694.
[28]	YOON JG, KIM MH, JANG M, et al. Molecular characterization of biliary tract cancer predicts chemotherapy and programmed death 1/programmed death-ligand 1 blockade responses[J]. Hepatology, 2021, 74(4): 1914-1931. DOI: 10.1002/hep.31862.
[29]	GOEPPERT B, ROESSLER S, RENNER M, et al. Mismatch repair deficiency is a rare but putative therapeutically relevant finding in non-liver fluke associated cholangiocarcinoma[J]. Br J Cancer, 2019, 120(1): 109-114. DOI: 10.1038/s41416-018-0199-2.
[30]	NAKAMURA H, ARAI Y, TOTOKI Y, et al. Genomic spectra of biliary tract cancer[J]. Nat Genet, 2015, 47(9): 1003-1010. DOI: 10.1038/ng.3375.
[31]	SAWASDEE N, THEPMALEE C, SUJJITJOON J, et al. Gemcitabine enhances cytotoxic activity of effector T-lymphocytes against chemo-resistant cholangiocarcinoma cells[J]. Int Immunopharmacol, 2020, 78: 106006. DOI: 10.1016/j.intimp.2019.106006.
[32]	MORISAKI T, UMEBAYASHI M, KIYOTA A, et al. Combining cetuximab with killer lymphocytes synergistically inhibits human cholangiocarcinoma cells in vitro[J]. Anticancer Res, 2012, 32(6): 2249-2256.
[33]	KVERNELAND AH, CHAMBERLAIN CA, BORCH TH, et al. Adoptive cell therapy with tumor-infiltrating lymphocytes supported by checkpoint inhibition across multiple solid cancer types[J]. J Immunother Cancer, 2021, 9(10): e003499. DOI: 10.1136/jitc-2021-003499.
[34]	TRAN E, TURCOTTE S, GROS A, et al. Cancer immunotherapy based on mutation-specific CD4⁺ T cells in a patient with epithelial cancer[J]. Science, 2014, 344(6184): 641-645. DOI: 10.1126/science.1251102.
[35]	PRICKETT TD, CRYSTAL JS, COHEN CJ, et al. Durable complete response from metastatic melanoma after transfer of autologous T cells recognizing 10 mutated tumor antigens[J]. Cancer Immunol Res, 2016, 4(8): 669-678. DOI: 10.1158/2326-6066.CIR-15-0215.
[36]	TRAN E, ROBBINS PF, LU YC, et al. T-Cell transfer therapy targeting mutant KRAS in cancer[J]. N Engl J Med, 2016, 375(23): 2255-2262. DOI: 10.1056/NEJMoa1609279.
[37]	KOUKOURAKIS IM, GKEGKA AG, XANTHOPOULOU E, et al. Prognostic and predictive relevance of tumor-infiltrating lymphocytes in squamous cell head-neck cancer patients treated with radical radiotherapy/chemo-radiotherapy[J]. Curr Oncol, 2022, 29(6): 4274-4284. DOI: 10.3390/curroncol29060342.
[38]	AOKI Y, TAKAKUWA K, KODAMA S, et al. Use of adoptive transfer of tumor-infiltrating lymphocytes alone or in combination with cisplatin-containing chemotherapy in patients with epithelial ovarian cancer[J]. Cancer Res, 1991, 51(7): 1934-1939.
[39]	CHAMBERLAIN CA, BENNETT EP, KVERNELAND AH, et al. Highly efficient PD-1-targeted CRISPR-Cas9 for tumor-infiltrating lymphocyte-based adoptive T cell therapy[J]. Mol Ther Oncolytics, 2022, 24: 417-428. DOI: 10.1016/j.omto.2022.01.004.
[40]	ZHANG L, MORGAN RA, BEANE JD, et al. Tumor-infiltrating lymphocytes genetically engineered with an inducible gene encoding interleukin-12 for the immunotherapy of metastatic melanoma[J]. Clin Cancer Res, 2015, 21(10): 2278-2288. DOI: 10.1158/1078-0432.CCR-14-2085.
[41]	FORGET MA, TAVERA RJ, HAYMAKER C, et al. A novel method to generate and expand clinical-grade, genetically modified, tumor-infiltrating lymphocytes[J]. Front Immunol, 2017, 8: 908. DOI: 10.3389/fimmu.2017.00908.
[42]	GERARD CL, DELYON J, WICKY A, et al. Turning tumors from cold to inflamed to improve immunotherapy response[J]. Cancer Treat Rev, 2021, 101: 102227. DOI: 10.1016/j.ctrv.2021.102227.