Xing Li
Dinesh Kumar Ahirwar2- 1Department of Medical Oncology and Guangdong Key Laboratory of Liver Disease Research, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
- 2Department of Bioscience & Bioengineering, Indian Institute of Technology Jodhpur, Karwar, Rajasthan, India
Editorial on the Research Topic
Myeloid-derived suppressor cells in inflammation and its complications and cancers
Obstruction of the differentiation and development of myeloid progenitor cells is a critical immune system disorder that occurs under physiological conditions including cancer, chronic or acute inflammations (1–5). In normal physiological conditions, common myeloid progenitor cells (CMP) differentiate into megakaryocyte erythroid progenitor cells (MEP) and granulocyte-monocyte progenitor (GMP) (6). When the process of GMP differentiation and development towards granulocytes and monocytes is blocked, the immature myeloid cells develop immune suppressive function without gaining proinflammatory capabilities. These cells were defined as myeloid-derived suppressor cell (MDSCs) (7, 8).
In this Research Topic focused on MDSC in chronic inflammation and cancer, several interesting studies investigated the roles of MDSCs in pathologic progression from inflammation to malignancies. While immune suppressive function is a basic feature of MDSCs (8, 9), their roles in chronic inflammatory diseases are controversial (1). In different conditions, MDSC may either promote or relieve chronic diseases. Our previous studies found that MDSC relieved chronic inflammatory diseases, including asthma and neonatal necrotizing enterocolitis (10–12). In vitro generated MDSC by lactoferrin have also been shown to relieve bleomycin induced interstitial pneumonia (11). However, Liu et al. reported that idiopathic pulmonary fibrosis (IPF) related MDSC actually promoted IPF by activating lung fibroblasts and myofibroblast differentiation. Soluble B7H3 generated by lung fibroblasts induced and chemoattracted monocytic MDSCs (M-MDSCs) to IPF lesions, which in turn activated lung fibroblasts and myofibroblast differentiation. The mechanism of B7H3-dependent MDSCs in IPF displayed a disease-specific manner, indicating that glucocorticoids suppressed the level of M-MDSC. However, glucocorticoids have been reported to induce MDSC in other conditions (11).
In addition to activating myofibroblast differentiation in IPF, MDSCc aggravate Helicobacter-induced malignancies. Schlafen4+ MDSCs have been found to be a disease-specific MDSC in Helicobacter-induced gastric metaplasia and malignancies (13–17) by Ding et al. In this Research Topic, they revealed the role of GTPases in Schlafen4+ MDSCs. They found that disruption of Slfn4 or pharmacologic inhibition of PED5/6 after Helicobacter infection suppressed MDSC function and mitigated development of spasmolytic polypeptide-expressing metaplasia (SPEM). The role of MDSC in peritoneal metastases from gastric cancer was evaluated by Takahashi et al. They found that M2-type macrophages were significantly higher in patients with peritoneal metastases. CD14+ monocyte populations displayed different markers between patients with or without peritoneal metastases. Their results indicated the potential role of M-MDSC in peritoneal metastases.
Not only the pathological role of MDSCs, but their prognostic value is also under active investigation for multiple diseases (18, 19). Petrova et al. found that melanoma patients without visible metastasis were characterized by the absence of MDSC immunosuppressive activity. MDSC frequency was significantly increased in non-responders to immune checkpoint inhibitors (ICIs) treatment compared to responders. However, the methodology for studying MDSCs are not easily standardized. Previous studies have found that human MDSCs need to be studied on fresh PBMC. G-MDSC can be studied with delay, but M-MDSC should be studied no later than 4 h after blood draw (20). The quality control of T cell suppressive function experiments is even more strict, according to our experience.
Modulate the immune suppressive function of MDSC has been investigated to relieve MDSC mediated pathologic progress (10–12). Our studies found lactoferrin induced MDSC relieved inflammatory diseases (10–12). Multiple MDSC eliminating methodology were developed as well (21). Kaul et al. found that slit2 induced M1 macrophages to enhances antitumor immunity, which could also be a potential method to suppress the development or suppressive function of MDSC.
In the last decade, extramedullary erythropoiesis has been found in the spleen in cases of anaemia, inflammation, and tumours, with a large number of CD71+erythroid progenitor cells (EPCs) accumulated (3–5, 22). There are two subtypes of CD71+EPCs. CD45+CD71+EPCs present immune suppressive function, which limits anti-infection immunity and promotes tumour development (3, 5, 23). CD45-EPCs promote tumour progression through secreting artemin (22). In 2022, a study found mixed development of erythroid and myeloid differentiation in the background of tumours. They found that EPCs had the potential to differentiate into myeloid cells, which was defined as erythroid-differentiated myeloid cells (EDMCs) (24), indicating that trans-differentiation of CMP progeny cells was a critical immune system disorders in the background of cancer. Our study found that CD45+EPCs were involved in chronic hepatitis B (CHB) (4) and CHB associated hepatocellular carcinoma (HCC) (23). CD45+EPCs inhibited HBsAg seroclearance during finite pegylated interferon treatment through LAG3 and TGF-β (4). CHB related CD45+EPCs presented myeloid cell morphology as well (4). Besides, EPCs, instead of MDSC, were the major immune suppressive cells in HCC microenvironment (23). Thus, our study indicated that EDMCs might be involved in the transformation of CHB to HCC. In summary, obstruction of the differentiation and development of myeloid progenitor cells lead to accumulation of MDSC and EPC, as well as EDMCs, which plays a critical role in inflammation, cancer and their transformation.
In conclusion, this Research Topic provides a comprehensive overview of the current understanding of MDSC in chronic inflammation and cancer. Although the roles of MDSCs in different diseases varied and is sometimes controversial, targeting MDSC might be a promising therapeutic strategy for multiple diseases, especial chronic inflammatory diseases and cancer. The mechanism underlies the obstruction of the differentiation and development of myeloid progenitor cells was disease specific and needs further investigation.
Author contributions
All authors listed have made a substantial, direct, and intellectual contribution to the work and approved it for publication.
Funding
This study was supported by the Guangdong Basic and Applied Basic Research Foundation (No. 2021A1515011022, 2023A1515012544, and 2022A1515012659), and Tip-top Scientific and Technical Innovative Youth Talents of the Third Affiliated Hospital of Sun Yat-sen University.
Conflict of interest
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
Publisher’s note
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References
1. Sanchez-Pino MD, Dean MJ, Ochoa AC. Myeloid-derived suppressor cells (MDSC): When good intentions go awry. Cell Immunol (2021) 362:104302. doi: 10.1016/j.cellimm.2021.104302
2. Cao Y, He Y, Wang X, Liu Y, Shi K, Zheng Z, et al. Polymorphonuclear myeloid-derived suppressor cells attenuate allergic airway inflammation by negatively regulating group 2 innate lymphoid cells. Immunology (2019) 156(4):402–12. doi: 10.1111/imm.13040
3. Zhao L, He R, Long H, Guo B, Jia Q, Qin D, et al. Late-stage tumors induce anemia and immunosuppressive extramedullary erythroid progenitor cells. Nat Med (2018) 24(10):1536–44. doi: 10.1038/s41591-018-0205-5
4. Pang XQ, Li X, Zhu WH, Huang RK, Mo ZS, Huang ZX, et al. LAG3(+) erythroid progenitor cells inhibit HBsAg seroclearance during finite pegylated interferon treatment through LAG3 and TGF-beta. Antiviral Res (2023) 213:105592. doi: 10.1016/j.antiviral.2023.105592
5. Elahi S, Ertelt JM, Kinder JM, Jiang TT, Zhang X, Xin L, et al. Immunosuppressive CD71+ erythroid cells compromise neonatal host defence against infection. Nature (2013) 504(7478):158–62. doi: 10.1038/nature12675
6. Kaushansky K. Lineage-specific hematopoietic growth factors. N Engl J Med (2006) 354(19):2034–45. doi: 10.1056/NEJMra052706
7. Gabrilovich DI. Myeloid-derived suppressor cells. Cancer Immunol Res (2017) 5(1):3–8. doi: 10.1158/2326-6066.CIR-16-0297
8. Kumar V, Patel S, Tcyganov E, Gabrilovich DI. The nature of myeloid-derived suppressor cells in the tumor microenvironment. Trends Immunol (2016) 37(3):208–20. doi: 10.1016/j.it.2016.01.004
9. Bronte V, Brandau S, Chen SH, Colombo MP, Frey AB, Greten TF, et al. Recommendations for myeloid-derived suppressor cell nomenclature and characterization standards. Nat Commun (2016) 7:12150. doi: 10.1038/ncomms12150
10. He YM, Li X, Perego M, Nefedova Y, Kossenkov AV, Jensen EA, et al. Transitory presence of myeloid-derived suppressor cells in neonates is critical for control of inflammation. Nat Med (2018) 24(2):224–31. doi: 10.1038/nm.4467
11. Li X, Chen J, Chen YJ, Qiao YD, Zhao LY, Jiang N, et al. Dexamethasone and lactoferrin induced PMN-MDSCs relieved inflammatory adverse events of anti-cancer therapy without tumor promotion. Commun Biol (2021) 4(1):252. doi: 10.1038/s42003-021-01769-z
12. Liu Y, Perego M, Xiao Q, He Y, Fu S, He J, et al. Lactoferrin-induced myeloid-derived suppressor cell therapy attenuates pathologic inflammatory conditions in newborn mice. J Clin Invest (2019) 129(10):4261–75. doi: 10.1172/JCI128164
13. Ding L, Chakrabarti J, Sheriff S, Li Q, Thi Hong HN, Sontz RA, et al. Toll-like receptor 9 pathway mediates Schlafen(+)-MDSC polarization during helicobacter-induced gastric metaplasias. Gastroenterology (2022) 163(2):411–25 e4. doi: 10.1053/j.gastro.2022.04.031
14. Xiang X, Wu Y, Li H, Li C, Yan L, Li Q. Plasmacytoid dendritic cell-derived type I interferon is involved in helicobacter pylori infection-induced differentiation of schlafen 4-expressing myeloid-derived suppressor cells. Infect Immun (2021) 89(11):e0040721. doi: 10.1128/IAI.00407-21
15. Ding L, Hayes MM, Photenhauer A, Eaton KA, Li Q, Ocadiz-Ruiz R, et al. Schlafen 4-expressing myeloid-derived suppressor cells are induced during murine gastric metaplasia. J Clin Invest (2016) 126(8):2867–80. doi: 10.1172/JCI82529
16. Ding L, Li Q, Chakrabarti J, Munoz A, Faure-Kumar E, Ocadiz-Ruiz R, et al. MiR130b from Schlafen4(+) MDSCs stimulates epithelial proliferation and correlates with preneoplastic changes prior to gastric cancer. Gut (2020) 69(10):1750–61. doi: 10.1136/gutjnl-2019-318817
17. Merchant JL, Ding L. Hedgehog signaling links chronic inflammation to gastric cancer precursor lesions. Cell Mol Gastroenterol Hepatol (2017) 3(2):201–10. doi: 10.1016/j.jcmgh.2017.01.004
18. Chen J, Chen YJ, Jiang N, Xu JL, Liang ZM, Bai MJ, et al. Neutrophil-to-apolipoprotein A1 ratio predicted overall survival in hepatocellular carcinoma receiving transarterial chemoembolization. Oncologist (2021) 26(8):e1434–44. doi: 10.1002/onco.13743
19. Fan R, De Beule N, Maes A, De Bruyne E, Menu E, Vanderkerken K, et al. The prognostic value and therapeutic targeting of myeloid-derived suppressor cells in hematological cancers. Front Immunol (2022) 13:1016059. doi: 10.3389/fimmu.2022.1016059
20. Grutzner E, Stirner R, Arenz L, Athanasoulia AP, Schrodl K, Berking C, et al. Kinetics of human myeloid-derived suppressor cells after blood draw. J Transl Med (2016) 14:2. doi: 10.1186/s12967-015-0755-y
21. Talmadge JE, Gabrilovich DI. History of myeloid-derived suppressor cells. Nat Rev Cancer (2013) 13(10):739–52. doi: 10.1038/nrc3581
22. Han Y, Liu Q, Hou J, Gu Y, Zhang Y, Chen Z, et al. Tumor-induced generation of splenic erythroblast-like ter-cells promotes tumor progression. Cell (2018) 173(3):634–48.e12. doi: 10.1016/j.cell.2018.02.061
23. Chen J, Qiao YD, Li X, Xu JL, Ye QJ, Jiang N, et al. Intratumoral CD45(+)CD71(+) erythroid cells induce immune tolerance and predict tumor recurrence in hepatocellular carcinoma. Cancer Lett (2021) 499:85–98. doi: 10.1016/j.canlet.2020.12.003
Keywords: myeloid-derived suppressor cells, chronic inflammation, cancer, extramedullary erythropoiesis, erythroid progenitor cells
Citation: Li X, Ahirwar DK and Wu X-Y (2023) Editorial: Myeloid-derived suppressor cells in inflammation and its complications and cancers. Front. Immunol. 14:1240415. doi: 10.3389/fimmu.2023.1240415
Received: 15 June 2023; Accepted: 10 July 2023;
Published: 18 July 2023.
Edited and Reviewed by:
Pietro Ghezzi, University of Urbino Carlo Bo, ItalyCopyright © 2023 Li, Ahirwar and Wu. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
*Correspondence: Xing Li, bGl4aW5nOUBtYWlsLnN5c3UuZWR1LmNu