Myeloid-derived suppressor-like cells – a potential biomarker for prognosis of colorectal cancer?

Irina Brčerević; Radoje Doder; Danilo Vojvodić; Nenad Perišić; Stanko  Petrović

doi:10.2298/VSP220117083B

Irina Brčerević Military Medical Academy, Clinic for Gastroenterology and Hepatology, Belgrade, Serbia
Radoje Doder Military Medical Academy, Clinic for Gastroenterology and Hepatology, Belgrade, Serbi a
Danilo Vojvodić University of Defence, Faculty of Medicine of the Military Medical Academy, Belgrade, Serbia
Nenad Perišić Military Medical Academy, Clinic for Gastroenterology and Hepatology, Belgrade, Serbia
Stanko Petrović Military Medical Academy, Clinic for Gastroenterology and Hepatology, Belgrade, Serbia

DOI: https://doi.org/10.2298/VSP220117083B

Keywords: biomarkers, colorectal neoplasms, myeloid-derived suppressor cells, prognosis, treatment outcome

Abstract

Background/Aim. Myeloid-derived suppressor cells (MDSCs) represent a heterogeneous group of immature cells that have the ability to inhibit both the innate and adaptive immune response. Due to their immunosuppressive effect, MDSCs can promote the growth and progression of cancer. Colorectal cancer (CRC) is one of the most common cancers in the general population for whose advanced stages there is still no successful therapy. In addition to contributing to the development and spread of CRC, MDSCs could potentially be seen as markers of its prognosis. The aim of the study was to examine the potential prognostic role of peripheral blood MDSC counts in CRC patients. Methods. This prospective study analyzed the possibility of using CD16^low granulocytes and monocytic MDSC (M-MDSC) like cells, as well as neutrophil-to-lymphocyte ratio (NLR), lymphocyte-to-monocyte ratio (LMR), CD16^high/CD16^low granulocytes ratio, and monocyte-to-M-MDSC like cells ratio, before the start of the treatment, as biomarkers for overall survival (OS) in patients with CRC. The hazard ratio with the corresponding confidence interval of 95% (95% CI) was calculated to evaluate the prognostic role of MDSC in CRC. Results. The analysis was performed in 47 patients with stages III and IV of CRC according to the TNM/AJCC disease classification. Reliable data were obtained from 32 patients. Patient blood samples were taken before the possible start of treatment (surgery, chemotherapy). Increased percentages and absolute values of CD16^low granulocytes, as well as absolute values of M-MDSC like cells, were associated with shorter OS (p < 0.0066, p < 0.0013, and p < 0.0119, respectively). The relationship between CD16^high/CD16^low granulocytes ratio and monocyte/M-MDSC like cells ratio with OS indicated the existence of positive correlations between these parameters, where the higher value of this relationship indicated longer OS of patients (p < 0.0054 and p < 0.0148, respectively). The relationship between OS and NLR showed a statistically significant inverse correlation (p = 0.0349). No statistical significance was found in the relationship between OS and LMR. Conclusion. Percentages and absolute numbers of CD16^low granulocytes, as well as the absolute numbers of M-MDSC like cells, the CD16^high/CD16^low granulocytes ratio, monocyte/M-MDSC like cells ratio, and NLR ratio, may be reliable indicators of OS in patients with CRC.

References

1. Sung H, Ferlay J, Siegel RL, Laversanne M, Soerjomataram I, Jemal A, et al. Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries. CA Cancer J Clin 2021; 71(3): 209‒49.

2. World Health Organization. The Global Cancer Observatory. Available from: https//www. gco.iarc.fr/today/data/factsheets/
populations/688-serbia-fact-sheets.pdf [latest publications 2022 August 18].

3. Aurif F, Kaur H, Chio JPG, Kittaneh M, Malik BH. The Association Between Cholecystectomy and Colorectal Cancer in the Female Gender. Cureus 2021; 13(12): e20113.

4. Yang LP, Wang ZX, Zhang R, Zhou N, Wang AM, Liang W, et al. Association between cigarette smoking and colorectal cancer sidedness: A multi-center big-data platform-based analysis. J Transl Med 2021; 19(1): 150.

5. Yu P, Fu YX. Tumor-infiltrating T lymphocytes: friends or foes? Lab Invest 2006; 86(3): 231‒45.

6. Duwe AK, Singhal SK. The immunoregulatory role of bone marrow. I. Suppression of the induction of antibody responses to T-dependent and T-independent antigens by cells in the bone marrow. Cell Immunol 1979; 43(2): 362‒71.

7. Talmadge JE, Gabrilovich DI. History of myeloid-derived suppressor cells. Nat Rev Cancer 2013; 13(10): 739‒52.

8. 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.

9. Condamine T, Dominguez GA, Youn JI, Kossenkov AV, Mony S, Alicea-Torres K, et al. Lectin-type oxidized LDL receptor-1 distinguishes population of human polymorphonuclear myeloid-derived suppressor cells in cancer patients. Sci Immunol 2016; 1(2): aaf8943.

10. Ma P, Beatty PL, McKolanis J, Brand R, Schoen RE, Finn OJ. Circulating Myeloid-Derived Suppressor Cells (MDSC) That Accumulate in Premalignancy Share Phenotypic and Functional Characteristics With MDSC in Cancer. Front Immunol 2019; 10: 1401.

11. Gabrilovich DI, Nagaraj S. Myeloid-derived suppressor cells as regulators of the immune system. Nat Rev Immunol 2009; 9(3): 162‒74.

12. Tcyganov E, Mastio J, Chen E, Gabrilovich DI. Plasticity of myeloid-derived suppressor cells in cancer. Curr Opin Immunol 2018; 51: 76‒82

13. Köstlin-Gille N, Gille C. Myeloid-Derived Suppressor Cells in Pregnancy and the Neonatal Period. Front Immunol 2020; 11: 584712.

14. Medina E, Hartl D. Myeloid-Derived Suppressor Cells in Infection: A General Overview. J Innate Immun 2018; 10(5‒6): 407‒13.

15. Wang YG, Xiong X, Chen ZY, Liu KL, Yang JH, Wen Q, et al. Expansion of myeloid-derived suppressor cells in patients with acute coronary syndrome. Cell Physiol Biochem 2015; 35(1): 292‒304.

16. Ostrand-Rosenberg S. Myeloid derived-suppressor cells: their role in cancer and obesity. Curr Opin Immunol 2018; 51: 68‒75.

17. Friedrich K, Sommer M, Strobel S, Thrum S, Blüher M, Wagner U, et al. Perturbation of the Monocyte Compartment in Human Obesity. Front Immunol 2019; 10: 1874.

18. Schrijver IT, Théroude C, Roger T. Myeloid-Derived Suppressor Cells in Sepsis. Front Immunol 2019; 10: 327.

19. Thome AD, Faridar A, Beers DR, Thonhoff JR, Zhao W, Wen S, et al. Functional alterations of myeloid cells during the course of Alzheimer's disease. Mol Neurodegener 2018; 13(1): 61.

20. Chen S, Liu Y, Niu Y, Xu Y, Zhou Q, Xu X, et al. Increased abundance of myeloid-derived suppressor cells and Th17 cells in peripheral blood of newly-diagnosed Parkinson's disease patients. Neurosci Lett 2017; 648: 21‒5.

21. Toor SM, Syed Khaja AS, El Salhat H, Bekdache O, Kanbar J, Jaloudi M, et al. Increased Levels of Circulating and Tumor-Infiltrating Granulocytic Myeloid Cells in Colorectal Cancer Patients. Front Immunol 2016; 7: 560.

22. Zhang B, Wang Z, Wu L, Zhang M, Li W, Ding J, et al. Circulating and tumor-infiltrating myeloid-derived suppressor cells in patients with colorectal carcinoma. PLoS One 2013; 8(2): e57114.

23. Kusmartsev S, Gabrilovich DI. Effect of tumor-derived cytokines and growth factors on differentiation and immune suppressive features of myeloid cells in cancer. Cancer Metastasis Rev 2006; 25(3): 323‒31.

24. Meirow Y, Kanterman J, Baniyash M. Paving the Road to Tumor Development and Spreading: Myeloid-Derived Suppressor Cells are Ruling the Fate. Front Immunol 2015; 6: 523.

25. Saleem SJ, Martin RK, Morales JK, Sturgill JL, Gibb DR, Graham L, et al. Cutting edge: mast cells critically augment myeloid-derived suppressor cell activity. J Immunol 2012; 189(2): 511‒5.

26. Obermajer N, Muthuswamy R, Lesnock J, Edwards RP, Kalinski P. Positive feedback between PGE2 and COX2 redirects the differentiation of human dendritic cells toward stable myeloid-derived suppressor cells. Blood 2011; 118(20): 5498‒505.

27. Chouaib S, Umansky V, Kieda C. The role of hypoxia in shaping the recruitment of proangiogenic and immunosuppressive cells in the tumor microenvironment. Contemp Oncol (Pozn) 2018; 22(1A): 7‒13.

28. Chun E, Lavoie S, Michaud M, Gallini CA, Kim J, Soucy G, et al. CCL2 Promotes Colorectal Carcinogenesis by Enhancing Polymorphonuclear Myeloid-Derived Suppressor Cell Population and Function. Cell Rep 2015; 12(2): 244‒57.

29. OuYang LY, Wu XJ, Ye SB, Zhang RX, Li ZL, Liao W, et al. Tumor-induced myeloid-derived suppressor cells promote tumor progression through oxidative metabolism in human colorectal cancer. J Transl Med 2015; 13: 47.

30. Wang Y, Yin K, Tian J, Xia X, Ma J, Tang X, et al. Granulocytic Myeloid-Derived Suppressor Cells Promote the Stemness of Colorectal Cancer Cells through Exosomal S100A9. Adv Sci (Weinh) 2019; 6(18): 1901278.

31. Sun HL, Zhou X, Xue YF, Wang K, Shen YF, Mao JJ, et al. Increased frequency and clinical significance of myeloid-derived suppressor cells in human colorectal carcinoma. World J Gastroenterol 2012; 18(25): 3303‒9.

32. Yang R, Cai TT, Wu XJ, Liu YN, He J, Zhang XS, et al. Tumour YAP1 and PTEN expression correlates with tumour-associated myeloid suppressor cell expansion and reduced survival in colorectal cancer. Immunology 2018; 155(2): 263‒72.

33. Tada K, Kitano S, Shoji H, Nishimura T, Shimada Y, Nagashima K, et al Pretreatment Immune Status Correlates with Progression-Free Survival in Chemotherapy-Treated Metastatic Colorectal Cancer Patients. Cancer Immunol Res 2016; 4(7): 592‒9.

34. Shimura T, Shibata M, Gonda K, Hayase S, Sakamoto W, Okayama H, et al. Prognostic impact of preoperative lymphocyte-to-monocyte ratio in patients with colorectal cancer with special reference to myeloid-derived suppressor cells. Fukushima J Med Sci 2018; 64(2): 64‒72.

35. Zou ZY, Liu HL, Ning N, Li SY, DU XH, Li R. Clinical significance of pre-operative neutrophil lymphocyte ratio and platelet lymphocyte ratio as prognostic factors for patients with colorectal cancer. Oncol Lett 2016; 11(3): 2241‒8.

36. Peng J, Li H, Ou Q, Lin J, Wu X, Lu Z, et al. Preoperative lymphocyte-to-monocyte ratio represents a superior predictor compared with neutrophil-to-lymphocyte and platelet-to-lymphocyte ratios for colorectal liver-only metastases survival. Onco Targets Ther 2017; 10: 3789‒99.

37. Stanojevic I, Miller K, Kandolf-Sekulovic L, Mijuskovic Z, Zolotarevski L, Jovic M, et al. A subpopulation that may correspond to granulocytic myeloid-derived suppressor cells reflects the clinical stage and progression of cutaneous melanoma. Int Immunol 2016; 28(2): 87‒97.

38. Bzowska M, Hamczyk M, Skalniak A, Guzik K. Rapid decrease of CD16 (FcγRIII) expression on heat-shocked neutrophils and their recognition by macrophages. J Biomed Biotechnol 2011; 2011: 284759.

39. Veglia F, Perego M, Gabrilovich D. Myeloid-derived suppressor cells coming of age. Nat Immunol 2018; 19(2): 108‒19.

40. Lu Y, Huang Y, Huang L, Xu Y, Wang Z, Li H, et al. CD16 expression on neutrophils predicts treatment efficacy of capecitabine in colorectal cancer patients. BMC Immunol 2020; 21(1): 46.

41. Afari M, Bhat T. Neutrophil to lymphocyte ratio (NLR) and cardiovascular diseases: an update. Expert Rev Cardiovasc Ther 2016; 14(5): 573‒7.

42. Fědorová L, Pilátová K, Selingerová I, Bencsiková B, Budinská E, Zwinsová B, et al. Circulating Myeloid-Derived Suppressor Cell Subsets in Patients with Colorectal Cancer - Exploratory Analysis of Their Biomarker Potential. Klin Onkol 2018; 31(Suppl 2): 88‒92.

43. Wang PF, Song SY, Wang TJ, Ji WJ, Li SW, Liu N, et al. Prognostic role of pretreatment circulating MDSCs in patients with solid malignancies: A meta-analysis of 40 studies. Oncoimmunology 2018; 7(10): e1494113.

44. Lang S, Bruderek K, Kaspar C, Höing B, Kanaan O, Dominas N, et al. Clinical Relevance and Suppressive Capacity of Human Myeloid-Derived Suppressor Cell Subsets. Clin Cancer Res 2018; 24(19): 4834‒44.

45. Sheng IY, Diaz-Montero CM, Rayman P, Wei W, Finke JH, Kim JS, et al. Blood Myeloid-Derived Suppressor Cells Correlate with Neutrophil-to-Lymphocyte Ratio and Overall Survival in Metastatic Urothelial Carcinoma. Target Oncol 2020; 15(2): 211‒20.

46. Qian C, Cai R, Zhang W, Wang J, Hu X, Zhang Y, et al. Neutrophil-Lymphocyte Ratio and Circulating Tumor Cells Counts Predict Prognosis in Gastrointestinal Cancer Patients. Front Oncol 2021; 11: 710704.

47. Sagiv JY, Michaeli J, Assi S, Mishalian I, Kisos H, Levy L, et al. Phenotypic diversity and plasticity in circulating neutrophil subpopulations in cancer. Cell Rep 2015; 10(4): 562‒73.

48. Olingy CE, Dinh HQ, Hedrick CC. Monocyte heterogeneity and functions in cancer. J Leukoc Biol 2019; 106(2): 309‒22.

49. Bergenfelz C, Larsson AM, von Stedingk K, Gruvberger-Saal S, Aaltonen K, Jansson S, et al. Systemic Monocytic-MDSCs Are Generated from Monocytes and Correlate with Disease Progression in Breast Cancer Patients. PLoS One 2015; 10(5): e0127028.

50. Wang L, Chang EW, Wong SC, Ong SM, Chong DQ, Ling KL. Increased myeloid-derived suppressor cells in gastric cancer correlate with cancer stage and plasma S100A8/A9 proinflammatory proteins. J Immunol 2013; 190(2): 794‒804.

51. Shen P, Wang A, He M, Wang Q, Zheng S. Increased circulating Lin(-/low) CD33(+) HLA-DR(-) myeloid-derived suppressor cells in hepatocellular carcinoma patients. Hepatol Res 2014; 44(6): 639‒50.

52. 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.

53. Wu WC, Sun HW, Chen HT, Liang J, Yu XJ, Wu C, et al. Circulating hematopoietic stem and progenitor cells are myeloid-biased in cancer patients. Proc Natl Acad Sci USA 2014; 111(11): 4221‒6.

54. Kim CH. Homeostatic and pathogenic extramedullary hematopoiesis. J Blood Med 2010; 1: 13‒9.

55. Choi J, Maeng HG, Lee SJ, Kim YJ, Kim DW, Lee HN, et al. Diagnostic value of peripheral blood immune profiling in colorectal cancer. Ann Surg Treat Res 2018; 94(6): 312‒21.