Myeloid-derived suppressor cells as biomarkers of the effectiveness of therapy with new biological agents in axial spondyloarthritis

Innate immune cells, including myeloid cells — myeloid derived suppressor cells (MDSCs) — are supposed to play an important role in the pathogenesis of axial spondyloarthritis (AxSp). Myeloid derived suppressor cells represent a heterogeneous population of immature cells capable of suppressing innate and adaptive immune responses with the most pronounced suppressor activity against T cells. Biological disease-modifying antirheumatic drugs (bDMARDs) can reduce the clinical and laboratory disease activity, but their effectiveness varies widely in different patients with AxSp. The present study is aimed at studying MDSCs subpopulations and their suppressive function depending on the response to bDMARD therapy in AxSp. The study included AxSp patients with a disease duration of 16.5 years (median); HLA-B27 (+) status was detected in 79% of cases. All patients received bDMARDs at least the past 12 weeks, including TNF inhibitors (etanercept, certolizumab pegol, adalimumab, or golimumab) or IL-17 inhibitors (secukinumab, ixekizumab, or netakimab). Percentage of granulocytic MDSCs (G-MDSCs, Lin^-HLA-DR-CD33⁺CD66b⁺), monocytic MDSCs (M-MDSCs, HLA-DR^low/-CD14⁺), MDSCs of early stage differentiation (E-MDSCs, Lin^-HLA-DR^- CD33⁺CD66b^-), as well as intracellular expression of arginase-1 was assessed by flow cytometry. Frequency of circulating MDSC subpopulations of patients with a stable response to bDMARDs (responders) did not differ significantly compared to healthy donors. Patients not responding to bDMARDs therapy showed increased relative and absolute number of E-MDSCs compared to healthy donors (p_U = 0.01 and p_U = 0.02, respectively) and the responders (p_U = 0.03 and p_U = 0.07, respectively). Increased percentage of E-MDSCs was positively correlated to disease activity — ESR (R_s = 0.821; p = 0.023), CRP (R_s = 0.714; p = 0.07) and ASDAS_CRP (R_s = 0.829; p = 0.042) in the non-responder group. Responder patients exhibited no correlation between disease activity and circulating MDSCs. The suppressor potential of MDSCs was analyzed by the intracellular expression of arginase-1 molecule which is involved in the inhibition of T cell response. Patients with the stable response were characterized by increased expression of arginase-1 in E-MDSCs compared to donors (p_U = 0.02). Non-responders did not demonstrate significant changes in Arg-1 expression, however, the percentage of arginase-1-expressing G-MDSCs was positively correlated to indexes ASDAS_ESR (R_s = 0.857; p = 0.014) and BASDAI (R_s = 0.785; p = 0.036). Thus, E-MDSCs as well as arginase-1 expression in MDSCs may serve as biomarkers of effectiveness bDMARD therapy, and act as potential candidate predictors of response to therapy in AxSp.

1. Biggioggero M., Favalli E.G. Ten-year drug survival of anti-TNF agents in the treatment of inflammatory arthritides: anti-TNF in inflammatory arthritides. Drug Dev. Res., 2014, Vol. 75, Suppl. 1, pp. S38-S41.

2. Exposito-Molinero R., Garda-Portales R., Lamua-Riazuelo L., Urruticoechea-Arana A., Navarro-Alonso P, Rey-Rey J., Fernandez-Prada M., Gonzalez Fernandez C.M. Effectiveness and retention rate of certolizumab pegol in spondyloarthritis. Real life data. Ann. Rheum. Dis., 2017, Vol. 69, Suppl. 10, 1550. doi: 10.1136/annrheumdis-2018-eular.5552.

3. Gabrilovich D.I. Myeloid-derived suppressor cells. Cancer Immunol. Res., 2017, Vol. 5, no. 1, pp. 3-8.

4. Gaydukova I.Z., Rebrov A.P., Aparkina A.V., Khondkaryan E.V. Stable high interleukin-17A concentration in patients with ankylosing spondylitis treated with tumor necrosis factor-а inhibitors during a year. Ter. Arch., 2017, Vol. 89, no. 4, pp. 80-85. (In Russ.)

5. Guo C., Hu F., Feng Zh., Li Ch., Shi L., Li Y., Liu H., Yu X., Wang H., Li J., Li Z., Wang X.-Y. Myeloid-derived suppressor cells have a proinflammatory role in the pathogenesis of autoimmune arthritis. Ann. Rheum. Dis., 2016, Vol. 75, no. 1, pp. 278-285.

6. Jiao Z., Hua S., Wang W., Wang H., Gao J., Wang X. Increased circulating myeloid-derived suppressor cells correlated negatively with Th17 cells in patients with rheumatoid arthritis. Scand. J. Rheumatol., 2013, Vol. 42, no. 2, pp. 85-90.

7. Lapshina S.A., Dubinina T.V., Badokin V.V., Bochkova A.G., Bugrova O.V., Gaidukova I.Z., Godzenko A.A., Dubikov A.A., Ivanova O.N., Korotaeva T.V., Nesmeyanova O.B., Nikishina I.P., Otteva E.N., Raskina T.A., Rebrov A.P., Rumyantseva O.A., Sitalo A.V., Smirnov A.V, Erdes S.F. Tumor necrosis factor-а inhibitors in the treatment of axial spondyloarthritis, including ankylosing spondylitis. Rheumatology Science and Practice, 2016, Vol. 54, Suppl. 1, pp. 75-79. (In Russ.)

8. Liu Y.F., Zhuang K.H., Chen B., Li P.W., Zhou X., Jiang H., Zhong L.M., Liu F.B. Expansion and activation of monocytic-myeloid-derived suppressor cell via STAT3/arginase-I signaling in patients with ankylosing spondylitis. Arthritis Res. Ther., 2018, Vol. 20, no. 1, 168. doi: 10.1186/s13075-018-1654-4

9. Morenkova A.Yu., Tikhonova M.A., Tyrinova T.V., Batorov E.V., Sizikov A.E., Chumasova O.A., Sulutian A.E., Ostanin A.A., Chernykh E.R. Expansion of myeloid-derived suppressor cells in the peripheral blood of patients with ankylosing spondylitis. Medical Immunology (Russia), 2021, Vol. 23, no. 2, pp. 327-338. (In Russ.) doi: 10.15789/1563-0625-EOM-2143.

10. Nuriakhmetova T.Yu., Abdulganieva D.I. Inefficacy of tumor necrosis factor а inhibitors and potential options for its overcoming. Practical Medicine, 2018, Vol. 16, no. 7 (part 2), pp. 72-80. (In Russ.)

11. Rajabinejad M., Salari F., Karaji A.G., Rezaiemanesh A. The role of myeloid-derived suppressor cells in the pathogenesis of rheumatoid arthritis; anti- or pro-inflammatory cells? Artif.Cells Nanomed. Biotechnol., 2019, Vol. 47, no. 1, pp. 4149-4158.

12. Tsukazaki H., Kaito T. The Role of the IL-23/IL-17 pathway in the pathogenesis of spondyloarthritis. Int. J. Mol. Sci., 2020, Vol. 21, no. 17, 6401. doi: 10.3390/ijms21176401.

13. Zhanga H., Wanga S., Huangb Y., Wanga H., Zhaoa J., Gaskinc F., Yanga N., Fud S.M. Myeloid-derived suppressor cells are proinflammatory and regulate collagen-induced arthritis through manipulating Th17 cell differentiation. Clin. Immunol., 2015, Vol. 157, no. 2, pp. 175-186.