Journal of Shanghai Jiao Tong University (Medical Science) >

2023 , Vol. 43 >Issue 10: 1317 - 1323

DOI: https://doi.org/10.3969/j.issn.1674-8115.2023.10.014

Review

Research progress of MDSCs-targeted immunotherapy for pancreatic cancer

  • Yahan QIN ,
  • Ke ZHANG ,
  • Mengyu ZHANG ,
  • Jie SHEN ,
  • Meiyu PENG
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  • Key Laboratory of Immune Microenvironment and Inflammatory Disease Research in Universities of Shandong Province, School of Basic Medicine, Weifang Medical University, Weifang 261053, China
PENG Meiyu, E-mail: pmy-107@163.com.

Received date: 2023-01-19

  Accepted date: 2023-07-07

  Online published: 2023-10-28

Supported by

National Natural Science Foundation of China(81972695);Shandong Province Higher Education Youth Talent Introduction Program "Immune Microenvironment and Inflammatory Disease Research Innovation Team"

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Abstract

Pancreatic cancer (PC) is a highly malignant digestive system tumor with a poor survival rate and prognosis. Most patients with pancreatic cancer have no obvious clinical manifestations in the early stage of the disease, and are found to be in the middle and late stage of the disease when they seek treatment.A unique and complex tumor microenvironment (TME) is formed during its development and evolution. Due to the occult nature of pancreatic cancer, for patients with advanced pancreatic cancer, some traditional treatment methods such as surgical resection and chemotherapy are very limited, and there is a lack of effective treatment programs. Of course, this is also related to the immunosuppression of the TME of pancreatic cancer. Some immunosuppressive cells, such as myeloid-derived suppressor cells (MDSCs) and regulatory T cells (Tregs), play an important immunosuppressive role in helping tumor immune escape. Therefore, it is considered to be a major difficulty in the treatment of pancreatic cancer. In recent years, with the in-depth study of TME, immunotherapy has gradually become a new therapeutic strategy, and has made great progress in the treatment of various malignant tumors. The study found that targeted MDSCs therapy is a new and effective treatment for pancreatic cancer.In this paper, we introduce the role of MDSCs in TME and their progress as potential targets for immunotherapy of pancreatic cancer, hoping to provide new directions for the treatment of pancreatic cancer and other tumors.

Key words： myeloid-derived suppressor cell (MDSC); pancreatic cancer; immunosuppression; targeted therapy

Cite this article

Yahan QIN , Ke ZHANG , Mengyu ZHANG , Jie SHEN , Meiyu PENG . Research progress of MDSCs-targeted immunotherapy for pancreatic cancer[J]. Journal of Shanghai Jiao Tong University (Medical Science), 2023 , 43(10) : 1317 -1323 . DOI: 10.3969/j.issn.1674-8115.2023.10.014

References

1 WU J, CAI J T. Dilemma and challenge of immunotherapy for pancreatic cancer[J]. Dig Dis Sci, 2021, 66(2): 359-368.
2 TSUCHIKAWA T, TAKEUCHI S, NAKAMURA T, et al. Clinical impact of chemotherapy to improve tumor microenvironment of pancreatic cancer[J]. World J Gastrointest Oncol, 2016, 8(11): 786-792.
3 GILLEN S, SCHUSTER T, MEYER ZUM BüSCHENFELDE C, et al. Preoperative/neoadjuvant therapy in pancreatic cancer: a systematic review and meta-analysis of response and resection percentages[J]. PLoS Med, 2010, 7(4): e1000267.
4 SHARMA V, AGGARWAL A, JACOB J, et al. Myeloid-derived suppressor cells: bridging the gap between inflammation and pancreatic adenocarcinoma[J]. Scand J Immunol, 2021, 93(5): e13021.
5 SARVEPALLI D, RASHID M U, RAHMAN A U, et al. Gemcitabine: a review of chemoresistance in pancreatic cancer[J]. Crit Rev Oncog, 2019, 24(2): 199-212.
6 THYAGARAJAN A, ALSHEHRI M S A, MILLER K L R, et al. Myeloid-derived suppressor cells and pancreatic cancer: implications in novel therapeutic approaches[J]. Cancers, 2019, 11(11): 1627.
7 DYSTHE M, PARIHAR R. Myeloid-derived suppressor cells in the tumor microenvironment[J]. Adv Exp Med Biol, 2020, 1224: 117-140.
8 KHALED Y S, AMMORI B J, 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.
9 GARGETT T, CHRISTO S N, HERCUS T R, et al. GM-CSF signalling blockade and chemotherapeutic agents act in concert to inhibit the function of myeloid-derived suppressor cells in vitro[J]. Clin Transl Immunology, 2016, 5(12): e119.
10 NAGARAJ S, GABRILOVICH D I. Tumor escape mechanism governed by myeloid-derived suppressor cells[J]. Cancer Res, 2008, 68(8): 2561-2563.
11 BRONTE V, BRANDAU S, CHEN S H, et al. Recommendations for myeloid-derived suppressor cell nomenclature and characterization standards[J]. Nat Commun, 2016, 7: 12150.
12 YOUN J I, NAGARAJ S, COLLAZO M, et al. Subsets of myeloid-derived suppressor cells in tumor-bearing mice[J]. J Immunol, 2008, 181(8): 5791-5802.
13 YOUN J I, GABRILOVICH D I. The biology of myeloid-derived suppressor cells: the blessing and the curse of morphological and functional heterogeneity[J]. Eur J Immunol, 2010, 40(11): 2969-2975.
14 GABRILOVICH D I, NAGARAJ S. Myeloid-derived suppressor cells as regulators of the immune system[J]. Nat Rev Immunol, 2009, 9(3): 162-174.
15 PENG M Y, ZHANG Q, LIU Y Q, et al. Apolipoprotein A-I mimetic peptide L-4F suppresses granulocytic-myeloid-derived suppressor cells in mouse pancreatic cancer[J]. Front Pharmacol, 2020, 11: 576.
16 MARVEL D, GABRILOVICH D I. Myeloid-derived suppressor cells in the tumor microenvironment: expect the unexpected[J]. J Clin Invest, 2015, 125(9): 3356-3364.
17 OSIPOV A, SAUNG M T, ZHENG L, et al. Small molecule immunomodulation: the tumor microenvironment and overcoming immune escape[J]. J Immunother Cancer, 2019, 7(1): 224.
18 PADOAN A, PLEBANI M, BASSO D. Inflammation and pancreatic cancer: focus on metabolism, cytokines, and immunity[J]. Int J Mol Sci, 2019, 20(3): 676.
19 APTE M V, XU Z, POTHULA S, et al. Pancreatic cancer: the microenvironment needs attention too![J]. Pancreatology, 2015, 15(4): S32-S38.
20 THAKUR A, SCHALK D, TOMASZEWSKI E, et al. Microenvironment generated during EGFR targeted killing of pancreatic tumor cells by ATC inhibits myeloid-derived suppressor cells through COX2 and PGE2 dependent pathway[J]. J Transl Med, 2013, 11: 35.
21 UZUNPARMAK B, SAHIN I H. Pancreatic cancer microenvironment: a current dilemma[J]. Clin Transl Med, 2019, 8(1): 2.
22 POREMBKA M R, MITCHEM J B, BELT B A, 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.
23 GABRILOVICH D I, OSTRAND-ROSENBERG S, BRONTE V. Coordinated regulation of myeloid cells by tumours[J]. Nat Rev Immunol, 2012, 12(4): 253-268.
24 LI H Q, HAN Y M, GUO Q L, et al. Cancer-expanded myeloid-derived suppressor cells induce anergy of NK cells through membrane-bound TGF-beta 1[J]. J Immunol, 2009, 182(1): 240-249.
25 SERAFINI P, MGEBROFF S, NOONAN K, et al. Myeloid-derived suppressor cells promote cross-tolerance in B-cell lymphoma by expanding regulatory T cells[J]. Cancer Res, 2008, 68(13): 5439-5449.
26 OSTRAND-ROSENBERG S. Myeloid-derived suppressor cells: more mechanisms for inhibiting antitumor immunity[J]. Cancer Immunol Immunother, 2010, 59(10): 1593-1600.
27 SZEFEL J, DANIELAK A, KRUSZEWSKI W J. Metabolic pathways of L-arginine and therapeutic consequences in tumors[J]. Adv Med Sci, 2019, 64(1): 104-110.
28 RODRíGUEZ P C, OCHOA A C. Arginine regulation by myeloid derived suppressor cells and tolerance in cancer: mechanisms and therapeutic perspectives[J]. Immunol Rev, 2008, 222: 180-191.
29 GALLEGO-ORTEGA D, LEDGER A, RODEN D L, et al. ELF5 drives lung metastasis in luminal breast cancer through recruitment of Gr1+ CD11b+ myeloid-derived suppressor cells[J]. PLoS Biol, 2015, 13(12): e1002330.
30 TALMADGE J E, GABRILOVICH D I. History of myeloid-derived suppressor cells[J]. Nat Rev Cancer, 2013, 13(10): 739-752.
31 BIAN Z, SHI L, VENKATARAMANI M, et al. Tumor conditions induce bone marrow expansion of granulocytic, but not monocytic, immunosuppressive leukocytes with increased CXCR2 expression in mice[J]. Eur J Immunol, 2018, 48(3): 532-542.
32 UMANSKY V, BLATTNER C, GEBHARDT C, et al. The role of myeloid-derived suppressor cells (MDSC) in cancer progression[J]. Vaccines, 2016, 4(4): 36.
33 TCYGANOV E, MASTIO J, CHEN E, et al. Plasticity of myeloid-derived suppressor cells in cancer[J]. Curr Opin Immunol, 2018, 51: 76-82.
34 HOLOKAI L, CHAKRABARTI J, LUNDY J, et al. Murine- and human-derived autologous organoid/immune cell co-cultures as pre-clinical models of pancreatic ductal adenocarcinoma[J]. Cancers, 2020, 12(12): 3816.
35 FARAJZADEH VALILOU S, KESHAVARZ-FATHI M, SILVESTRIS N, et al. The role of inflammatory cytokines and tumor associated macrophages (TAMs) in microenvironment of pancreatic cancer[J]. Cytokine Growth Factor Rev, 2018, 39: 46-61.
36 TADMOR T, ATTIAS D, POLLIACK A. Myeloid-derived suppressor cells: their role in haemato-oncological malignancies and other cancers and possible implications for therapy[J]. Br J Haematol, 2011, 153(5): 557-567.
37 DONG P, YAN Y, FAN Y J, et al. The role of myeloid-derived suppressor cells in the treatment of pancreatic cancer[J]. Technol Cancer Res Treat, 2022, 21: 15330338221142472.
38 HALABY M J, HEZAVEH K, LAMORTE S, et al. GCN2 drives macrophage and MDSC function and immunosuppression in the tumor microenvironment[J]. Sci Immunol, 2019, 4(42): eaax8189.
39 LAW A M K, VALDES-MORA F, GALLEGO-ORTEGA D. Myeloid-derived suppressor cells as a therapeutic target for cancer[J]. Cells, 2020, 9(3): 561.
40 SUZUKI E, SUN J, KAPOOR V, et al. Gemcitabine has significant immunomodulatory activity in murine tumor models independent of its cytotoxic effects[J]. Cancer Biol Ther, 2007, 6(6): 880-885.
41 SEVKO A, MICHELS T, VROHLINGS M, et al. Antitumor effect of paclitaxel is mediated by inhibition of myeloid-derived suppressor cells and chronic inflammation in the spontaneous melanoma model[J]. J Immunol, 2013, 190(5): 2464-2471.
42 GHANSAH T, VOHRA N, KINNEY K, et al. Dendritic cell immunotherapy combined with gemcitabine chemotherapy enhances survival in a murine model of pancreatic carcinoma[J]. Cancer Immunol Immunother, 2013, 62(6): 1083-1091.
43 MELANI C, SANGALETTI S, BARAZZETTA F M, et al. Amino-biphosphonate-mediated MMP-9 inhibition breaks the tumor-bone marrow axis responsible for myeloid-derived suppressor cell expansion and macrophage infiltration in tumor stroma[J]. Cancer Res, 2007, 67(23): 11438-11446.
44 GOEDEGEBUURE P, MITCHEM J B, POREMBKA M R, et al. Myeloid-derived suppressor cells: general characteristics and relevance to clinical management of pancreatic cancer[J]. Curr Cancer Drug Targets, 2011, 11(6): 734-751.
45 ISHERWOOD J, ARSHAD A, CHUNG W Y, et al. Myeloid derived suppressor cells are reduced and T regulatory cells stabilised in patients with advanced pancreatic cancer treated with gemcitabine and intravenous omega 3[J]. Ann Transl Med, 2020, 8(5): 172.
46 GHIRINGHELLI F, APETOH L. Enhancing the anticancer effects of 5-fluorouracil: current challenges and future perspectives[J]. Biomed J, 2015, 38(2): 111-116.
47 VINCENT J, MIGNOT G, CHALMIN F, et al. 5-Fluorouracil selectively kills tumor-associated myeloid-derived suppressor cells resulting in enhanced T cell-dependent antitumor immunity[J]. Cancer Res, 2010, 70(8): 3052-3061.
48 ANNELS N E, SHAW V E, GABITASS R F, et al. The effects of gemcitabine and capecitabine combination chemotherapy and of low-dose adjuvant GM-CSF on the levels of myeloid-derived suppressor cells in patients with advanced pancreatic cancer[J]. Cancer Immunol Immunother, 2014, 63(2): 175-183.
49 CONDAMINE T, KUMAR V, RAMACHANDRAN I R, et al. ER stress regulates myeloid-derived suppressor cell fate through TRAIL-R-mediated apoptosis[J]. J Clin Invest, 2014, 124(6): 2626-2639.
50 DOMINGUEZ G A, CONDAMINE T, MONY S, et al. Selective targeting of myeloid-derived suppressor cells in cancer patients using DS-8273a, an agonistic TRAIL-R2 antibody[J]. Clin Cancer Res, 2017, 23(12): 2942-2950.
51 PENG M Y, HUANG B Q, ZHANG Q, et al. Embelin inhibits pancreatic cancer progression by directly inducing cancer cell apoptosis and indirectly restricting IL-6 associated inflammatory and immune suppressive cells[J]. Cancer Lett, 2014, 354(2): 407-416.
52 GHANSAH T. A novel strategy for modulation of MDSC to enhance cancer immunotherapy[J]. Oncoimmunology, 2012, 1(6): 984-985.
53 VEGLIA F, PEREGO M, GABRILOVICH D. Myeloid-derived suppressor cells coming of age[J]. Nat Immunol, 2018, 19(2): 108-119.
54 SONG J, LEE J, KIM J, et al. Pancreatic adenocarcinoma up-regulated factor (PAUF) enhances the accumulation and functional activity of myeloid-derived suppressor cells (MDSCs) in pancreatic cancer[J]. Oncotarget, 2016, 7(32): 51840-51853.
55 NAGARAJ S, YOUN J I, WEBER H, et al. Anti-inflammatory triterpenoid blocks immune suppressive function of MDSCs and improves immune response in cancer[J]. Clin Cancer Res, 2010, 16(6): 1812-1823.
56 SANCTIS F D, SOLITO S, UGEL S, et al. MDSCs in cancer: conceiving new prognostic and therapeutic targets[J]. Biochim Biophys Acta, 2016, 1865(1): 35-48.
57 FLEMING V, HU X Y, WEBER R, et al. Targeting myeloid-derived suppressor cells to bypass tumor-induced immunosuppression[J]. Front Immunol, 2018, 9: 398.
58 SANFORD D E, BELT B A, PANNI R Z, et al. Inflammatory monocyte mobilization decreases patient survival in pancreatic cancer: a role for targeting the CCL2/CCR2 axis[J]. Clin Cancer Res, 2013, 19(13): 3404-3415.
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