Review of immunosuppressive tumor microenvironment of pancreatic cancer

doi:10.3969/j.issn.1674-8115.2021.08.018

Abstract

Abstract:

Pancreatic cancer is a highly malignant tumor. The difficulty of early diagnosis and scarcity of effective clinical treatment strategies lead to poor prognosis. Tumor microenvironment (TME) of pancreatic cancer is composed of tumor cells, immune cells, stromal cells, extracellular matrix and soluble factors. TME plays an important role in the development, progression, invasion and metastasis of tumors. The pancreatic cancer microenvironment has significant immune cell infiltration, which is highly immunosuppressive. On the one hand, tumor cells edit the immune system so that cancer cells cannot be recognized by the immune system; on the other hand, they can recruit and activate various immunosuppressive cells such as pancreatic stellate cells, myeloid-derived inhibitory cells, tumor-associated macrophages, regulatory T cells and so on. These immunosuppressive cells can secrete immunosuppressive molecules, affect the function of anti-tumor immune cells, inhibit the host′s anti-tumor immune response, lead to tumor immune escape, and promote tumor development and metastasis. In this review, the mechanisms and effects of these immunosuppressive components are discussed and the updated results of immunotherapy on pancreatic cancer are studied, which may provide novel insights on TME and immunotherapy of pancreatic cancer.

Key words: pancreatic cancer, tumor microenvironment (TME), immunosuppression, immunotherapy

CLC Number:

R735.9

Jing-wei LI, Li-wen WANG, Ling-xi JIANG, Qian ZHAN, Hao CHEN, Bai-yong SHEN. Review of immunosuppressive tumor microenvironment of pancreatic cancer[J]. JOURNAL OF SHANGHAI JIAOTONG UNIVERSITY (MEDICAL SCIENCE), 2021, 41(8): 1103-1108.

TrendMD

References 50

1	Fan JQ, Wang MF, Chen HL, et al. Current advances and outlooks in immunotherapy for pancreatic ductal adenocarcinoma[J]. Mol Cancer, 2020, 19(1): 32.
2	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.
3	Kamisawa T, Wood LD, Itoi T, et al. Pancreatic cancer[J]. Lancet, 2016, 388(10039):73-85.
4	Feig C, Gopinathan A, Neesse A, et al. The pancreas cancer microenvironment[J]. Clin Cancer Res, 2012, 18(16): 4266-4276.
5	叶辰, Zheng L, 原春辉. 胰腺癌免疫微环境及免疫治疗的前景与展望 [J]. 中华外科杂志, 2019, 57(1): 10-15.
6	Zheng L, Xue J, Jaffee EM, et al. Role of immune cells and immune-based therapies in pancreatitis and pancreatic ductal adenocarcinoma[J]. Gastroenterology, 2013, 144(6): 1230-1240.
7	卢军, 刘乔飞, 周立,等. 胰腺癌抑制性免疫微环境研究进展 [J]. 中华实验外科杂志, 2018, 35(8): 1393-1398.
8	Elyada E, Bolisetty M, Laise P, et al. Cross-species single-cell analysis of pancreatic ductal adenocarcinoma reveals antigen-presenting cancer-associated fibroblasts[J]. Cancer Discov, 2019, 9(8): 1102-1123.
9	Neesse A, Algül H, Tuveson DA, et al. Stromal biology and therapy in pancreatic cancer: a changing paradigm[J]. Gut, 2015, 64(9): 1476-1484.
10	Binenbaum Y, Na'ara S, Gil Z. Gemcitabine resistance in pancreatic ductal adenocarcinoma[J]. Drug Resist Updat, 2015, 23: 55-68.
11	von Ahrens D, Bhagat TD, Nagrath D, et al. The role of stromal cancer-associated fibroblasts in pancreatic cancer[J]. J Hematol Oncol, 2017, 10(1): 76.
12	Liu QF, Liao Q, Zhao YP. Chemotherapy and tumor microenvironment of pancreatic cancer[J]. Cancer Cell Int, 2017, 17(1): 1-17.
13	Zhang YF, Jiang SH, Hu LP, et al. Targeting the tumor microenvironment for pancreatic ductal adenocarcinoma therapy[J]. Chin Clin Oncol, 2019, 8(2): 18.
14	Feig C, Jones JO, Kraman M, et al. Targeting CXCL12 from FAP-expressing carcinoma-associated fibroblasts synergizes with anti-PD-L1 immunotherapy in pancreatic cancer[J]. PNAS, 2013, 110(50): 20212-20217.
15	Hartmann N, Giese NA, Giese T, et al. Prevailing role of contact guidance in intrastromal T-cell trapping in human pancreatic cancer[J]. Clin Cancer Res, 2014, 20(13): 3422-3433.
16	Özdemir BC, Pentcheva-Hoang T, Carstens JL, et al. Depletion of carcinoma-associated fibroblasts and fibrosis induces immunosuppression and accelerates pancreas cancer with reduced survival[J]. Cancer Cell, 2014, 25(6): 719-734.
17	徐敏, 王兴鹏. 胰腺星状细胞的发现及其意义 [J]. 胰腺病学, 2003, 3(z1): 25-27.
18	Allam A, Thomsen AR, Gothwal M, et al. Pancreatic stellate cells in pancreatic cancer: in focus[J]. Pancreatology, 2017, 17(4): 514-522.
19	Hamada S, Masamune A, Yoshida N, et al. IL-6/STAT3 plays a regulatory role in the interaction between pancreatic stellate cells and cancer cells[J]. Dig Dis Sci, 2016, 61(6): 1561-1571.
20	Tang D, Yuan Z, Xue X, et al. High expression of galectin-1 in pancreatic stellate cells plays a role in the development and maintenance of an immunosuppressive microenvironment in pancreatic cancer[J]. Int J Cancer, 2012, 130(10): 2337-2348.
21	Dineen SP, Lynn KD, Holloway SE, et al. Vascular endothelial growth factor receptor 2 mediates macrophage infiltration into orthotopic pancreatic tumors in mice[J]. Cancer Res, 2008, 68(11): 4340-4346.
22	Han X, Li Y, Xu Y, et al. Reversal of pancreatic desmoplasia by re-educating stellate cells with a tumour microenvironment-activated nanosystem[J]. Nat Commun, 2018, 9(1): 3390.
23	Veglia F, Perego M, Gabrilovich D. Myeloid-derived suppressor cells coming of age[J]. Nat Immunol, 2018, 19(2): 108-119.
24	Bronte V, Apolloni E, Cabrelle A, et al. Identification of a CD11b⁺/Gr-1⁺/CD31⁺ myeloid progenitor capable of activating or suppressing CD8⁺ T cells[J]. Blood, 2000, 96(12): 3838-3846.
25	Clark CE, Hingorani SR, Mick R, et al. Dynamics of the immune reaction to pancreatic cancer from inception to invasion[J]. Cancer Res, 2007, 67(19): 9518-9527.
26	Porembka MR, Mitchem JB, Belt BA, et al. Pancreatic adenocarcinoma induces bone marrow mobilization of myeloid-derived suppressor cells which promote primary tumor growth[J]. Cancer Immunol Immunother, 2012, 61(9): 1373-1385.
27	Khaled YS, Ammori BJ, Elkord E. Increased levels of granulocytic myeloid-derived suppressor cells in peripheral blood and tumour tissue of pancreatic cancer patients[J]. J Immunol Res, 2014, 2014: 879897.
28	Gabrilovich DI, Nagaraj S. Myeloid-derived suppressor cells as regulators of the immune system[J]. Nat Rev Immunol, 2009, 9(3): 162-174.
29	Huang B, Pan PY, Li Q, et al. Gr-1⁺CD115⁺ immature myeloid suppressor cells mediate the development of tumor-induced T regulatory cells and T-cell anergy in tumor-bearing host [J]. Cancer Res, 2006, 66(2): 1123-1131.
30	杨黎, 张毅. 肿瘤相关巨噬细胞研究进展[J]. 中国免疫学杂志, 2020, 36(2): 129-135.
31	蒋维香, 林彦俊, 岳建明. CD163⁺、CD204⁺巨噬细胞在胰腺癌组织中的浸润及临床意义[J]. 国际消化病杂志, 2019, 39(6): 436-439.
32	Kuang DM, Zhao Q, Peng C, et al. Activated monocytes in peritumoral stroma of hepatocellular carcinoma foster immune privilege and disease progression through PD-L1 [J]. J Exp Med, 2009, 206(6): 1327-1337.
33	Wang D, Yang L, Yue D, et al. Macrophage-derived CCL22 promotes an immunosuppressive tumor microenvironment via IL-8 in malignant pleural effusion[J]. Cancer Lett, 2019, 452: 244-253.
34	Li L, Yang L, Wang L, et al. Impaired T cell function in malignant pleural effusion is caused by TGF-β derived predominantly from macrophages[J]. Int J Cancer, 2016, 139(10): 2261-2269.
35	Zhang Y, Velez-Delgado A, Mathew E, et al. Myeloid cells are required for PD-1/PD-L1 checkpoint activation and the establishment of an immunosuppressive environment in pancreatic cancer[J]. Gut, 2017, 66(1): 124-136.
36	Kaneda MM, Cappello P, Nguyen AV, et al. Macrophage PI3Kγ drives pancreatic ductal adenocarcinoma progression [J]. Cancer Discov, 2016, 6(8):870-885.
37	黄德良, 朱新海, 盛良翮. 胰腺癌患者外周血中调节性T细胞和辅助性T细胞17的表达及其血清相关因子的检测[J]. 广东医学, 2017, 38(12): 1874-1876.
38	王秀超, 李鑫, 郝继辉. 调节性T细胞参与胰腺癌免疫微环境重塑的基础与转化研究进展[J]. 中国肿瘤临床, 2018, 45(18): 964-968.
39	Cao X, Cai SF, Fehniger TA, et al. Granzyme B and perforin are important for regulatory T cell-mediated suppression of tumor clearance[J]. Immunity, 2007, 27(4): 635-646.
40	Bauer CA, Kim EY, Marangoni F, et al. Dynamic Treg interactions with intratumoral APCs promote local CTL dysfunction[J]. J Clin Invest, 2014, 124(6): 2425-2440.
41	Jang JE, Hajdu CH, Liot C, et al. Crosstalk between regulatory T cells and tumor-associated dendritic cells negates anti-tumor immunity in pancreatic cancer[J]. Cell Rep, 2017, 20(3): 558-571.
42	Azuma T, Takahashi T, Kunisato A, et al. Human CD4⁺CD25⁺regulatory T cells suppress NKT cell functions[J]. Cancer Res, 2003, 63(15): 4516-4520.
43	Soares KC, Rucki AA, Kim V, et al. TGF-β blockade depletes T regulatory cells from metastatic pancreatic tumors in a vaccine dependent manner [J]. Oncotarget, 2015, 6(40): 43005-43015.
44	Gunderson AJ, Kaneda MM, Tsujikawa T, et al. Bruton tyrosine kinase-dependent immune cell cross-talk drives pancreas cancer[J]. Cancer Discov, 2016, 6(3): 270-285.
45	Daley D, Zambirinis CP, Seifert L, et al. γδ T cells support pancreatic oncogenesis by restraining αβ T cell activation [J]. Cell, 2016, 166(6): 1485-1499.e15.
46	Zamanakou M, Germenis AE, Karanikas V. Tumor immune escape mediated by indoleamine 2,3-dioxygenase [J]. Immunol Lett, 2007,111(2):69-75.
47	刘文增, 胡渊, 张彩. 胰腺癌的肿瘤微环境及其免疫治疗研究进展 [J]. 中国免疫学杂志, 2018, 34(12): 1901-1906.
48	Wu Q, Tian Y, Zhang J, et al. Functions of pancreatic stellate cell-derived soluble factors in the microenvironment of pancreatic ductal carcinoma[J]. Oncotarget, 2017, 8(60): 102721-102738.
49	Liang X, Sun J, Wu H, et al. PD-L1 in pancreatic ductal adenocarcinoma: a retrospective analysis of 373 Chinese patients using an in vitro diagnostic assay[J]. Diagn Pathol, 2018, 13(1): 5.
50	Royal RE, Levy C, Turner K, et al. Phase 2 trial of single agent Ipilimumab (anti-CTLA-4) for locally advanced or metastatic pancreatic adenocarcinoma[J]. J Immunother, 2010, 33(8): 828-833.

[1]	Xu-xin-yi LING, Yao ZHANG, Hua ZHONG. Research progress in screening non-small cell lung cancer patients who will benefit from immunotherapy [J]. JOURNAL OF SHANGHAI JIAOTONG UNIVERSITY (MEDICAL SCIENCE), 2021, 41(8): 1114-1119.
[2]	Paerhati NADINA, Yan YAN, Qian-ji CHE, Jing LUO, Xin-nan LIU, Bin LI. Application and prospect of chimeric antigen receptor-modified T cell therapy for glioblastoma [J]. JOURNAL OF SHANGHAI JIAOTONG UNIVERSITY (MEDICAL SCIENCE), 2021, 41(7): 982-986.
[3]	Yun-fang MA, Li-na PAN, Zhen LI, Bei-li GAO, Jia-an HU, Zhi-hong XU. Exploratory study on downregulation of PD-L1 in KRAS G12V-mutant non-small cell lung cancer cells by selumetinib [J]. JOURNAL OF SHANGHAI JIAOTONG UNIVERSITY (MEDICAL SCIENCE), 2021, 41(6): 741-748.
[4]	Lu-di YANG, Gao-ming WANG, Ren-hao HU, Xiao-hua JIANG, Ran CUI. Identification of core genes in pancreatic cancer progression by bioinformatics analysis [J]. JOURNAL OF SHANGHAI JIAOTONG UNIVERSITY (MEDICAL SCIENCE), 2021, 41(5): 571-578.
[5]	HE Chun-ming, YIN Hang, ZHENG Jia-jie, TANG Jian, FU Yu-jie, ZHAO Xiao-jing. Immunotherapy for lung cancer: immunosuppressive cells and intrapulmonary immunity [J]. JOURNAL OF SHANGHAI JIAOTONG UNIVERSITY (MEDICAL SCIENCE), 2020, 40(08): 1137-1142.
[6]	LIU Jie, QIU Xiao-chun. Research hotspots and trends of breast cancer stem cells [J]. JOURNAL OF SHANGHAI JIAOTONG UNIVERSITY (MEDICAL SCIENCE), 2020, 40(07): 881-888.
[7]	DAI Fei, WEI Jin-jin, TANG Xin-yue, CHEN Zheng, LIN Lin. Effect of sublingual immunotherapy on functions of effector T cells and regulatory T cells [J]. JOURNAL OF SHANGHAI JIAOTONG UNIVERSITY (MEDICAL SCIENCE), 2020, 40(05): 626-632.
[8]	LIANG Yu, JIANG Ming-jie, TIAN Ling. Advances in prostaglandin E2 reprogramming pancreatic cancer microenvironment [J]. , 2019, 39(8): 923-.
[9]	ZHAO Yi-si1, YU Ying-xi1, LIN Shi-hui2, XU Fang1, 2. Advances in the study of T cell immunity in invasive fungal infections secondary to sepsis [J]. , 2019, 39(11): 1325-.
[10]	LI Xiao, WANG Li. Immunomodulatory effect of myeloid-derived suppressor cell and its impact on tumor therapy [J]. , 2019, 39(10): 1204-.
[11]	LI Xia-yi, ZHENG Lei-zhen. Application of programmed cell death protein 1/programmed death-ligand 1 blockade in advanced gastric cancer treatment [J]. , 2018, 38(10): 1259-.
[12]	XIA Li, WANG Yue-ying . Chimeric antigen receptor T-cell immunotherapy and its applications in hematological malignancies immunotherapy [J]. , 2017, 37(6): 822-.
[13]	LI Xiao-ping, ZHANG Xiao-wei, GUO Wei-jian, et al. Expression of CD44 of patients with pancreatic cancer and its clinical significance [J]. , 2015, 35(9): 1354-.
[14]	HU Bin, SONG Shao-li. Progresses of treatment of pancreatic cancer [J]. , 2015, 35(3): 445-.
[15]	MA Cai-xia, LU Mei-fang, GE Li-ping, et al. Clinical evaluation of sublingual allergen specific immunotherapy in treatment to children with bronchial asthma and allergic rhinitis [J]. , 2014, 34(6): 873-.