DOI QR코드

DOI QR Code

The emerging role of myeloid-derived suppressor cells in radiotherapy

  • Kang, Changhee (Asan Institute for Life Sciences, Asan Medical Center, University of Ulsan College of Medicine) ;
  • Jeong, Seong-Yun (Asan Institute for Life Sciences, Asan Medical Center, University of Ulsan College of Medicine) ;
  • Song, Si Yeol (Department of Radiation Oncology, Asan Medical Center, University of Ulsan College of Medicine) ;
  • Choi, Eun Kyung (Department of Radiation Oncology, Asan Medical Center, University of Ulsan College of Medicine)
  • Received : 2019.12.16
  • Accepted : 2020.01.11
  • Published : 2020.03.31

Abstract

Radiotherapy (RT) has been used for decades as one of the main treatment modalities for cancer patients. The therapeutic effect of RT has been primarily ascribed to DNA damage leading to tumor cell death. Besides direct tumoricidal effect, RT affects antitumor responses through immune-mediated mechanism, which provides a rationale for combining RT and immunotherapy for cancer treatment. Thus far, for the combined treatment with RT, numerous studies have focused on the immune checkpoint inhibitors and have shown promising results. However, treatment resistance is still common, and one of the main resistance mechanisms is thought to be due to the immunosuppressive tumor microenvironment where myeloid-derived suppressor cells (MDSCs) play a crucial role. MDSCs are immature myeloid cells with a strong immunosuppressive activity. MDSC frequency is correlated with tumor progression, recurrence, negative clinical outcome, and reduced efficacy of immunotherapy. Therefore, increasing efforts to target MDSCs have been made to overcome the resistance in cancer treatments. In this review, we focus on the role of MDSCs in RT and highlight growing evidence for targeting MDSCs in combination with RT to improve cancer treatment.

Keywords

References

  1. Toulany M. Targeting DNA double-strand break repair pathways to improve radiotherapy response. Genes (Basel) 2019;10:25. https://doi.org/10.3390/genes10010025
  2. Lauber K, Ernst A, Orth M, Herrmann M, Belka C. Dying cell clearance and its impact on the outcome of tumor radiotherapy. Front Oncol 2012;2:116. https://doi.org/10.3389/fonc.2012.00116
  3. Diegeler S, Hellweg CE. Intercellular communication of tumor cells and immune cells after exposure to different ionizing radiation qualities. Front Immunol 2017;8:664. https://doi.org/10.3389/fimmu.2017.00664
  4. Campian JL, Ye X, Brock M, Grossman SA. Treatment-related lymphopenia in patients with stage III non-small-cell lung cancer. Cancer Invest 2013;31:183-8. https://doi.org/10.3109/07357907.2013.767342
  5. Ellsworth SG. Field size effects on the risk and severity of treatment-induced lymphopenia in patients undergoing radiation therapy for solid tumors. Adv Radiat Oncol 2018;3:512-9. https://doi.org/10.1016/j.adro.2018.08.014
  6. Venkatesulu BP, Mallick S, Lin SH, Krishnan S. A systematic review of the influence of radiation-induced lymphopenia on survival outcomes in solid tumors. Crit Rev Oncol Hematol 2018;123:42-51. https://doi.org/10.1016/j.critrevonc.2018.01.003
  7. Deng L, Liang H, Xu M, et al. STING-dependent cytosolic DNA sensing promotes radiation-induced type I interferon-dependent antitumor immunity in immunogenic tumors. Immunity 2014;41:843-52. https://doi.org/10.1016/j.immuni.2014.10.019
  8. Burnette BC, Liang H, Lee Y, et al. The efficacy of radiotherapy relies upon induction of type I interferon-dependent innate and adaptive immunity. Cancer Res 2011;71:2488-96. https://doi.org/10.1158/0008-5472.CAN-10-2820
  9. Apetoh L, Ghiringhelli F, Tesniere A, et al. Toll-like receptor 4-dependent contribution of the immune system to anticancer chemotherapy and radiotherapy. Nat Med 2007;13:1050-9. https://doi.org/10.1038/nm1622
  10. Roberts EW, Broz ML, Binnewies M, et al. Critical role for CD103(+)/CD141(+) dendritic cells bearing CCR7 for tumor antigen trafficking and priming of T cell immunity in melanoma. Cancer Cell 2016;30:324-36. https://doi.org/10.1016/j.ccell.2016.06.003
  11. Demaria S, Ng B, Devitt ML, et al. Ionizing radiation inhibition of distant untreated tumors (abscopal effect) is immune mediated. Int J Radiat Oncol Biol Phys 2004;58:862-70. https://doi.org/10.1016/j.ijrobp.2003.09.012
  12. Weichselbaum RR, Liang H, Deng L, Fu YX. Radiotherapy and immunotherapy: a beneficial liaison? Nat Rev Clin Oncol 2017;14:365-79. https://doi.org/10.1038/nrclinonc.2016.211
  13. Sato H, Niimi A, Yasuhara T, et al. DNA double-strand break repair pathway regulates PD-L1 expression in cancer cells. Nat Commun 2017;8:1751. https://doi.org/10.1038/s41467-017-01883-9
  14. Shevtsov M, Sato H, Multhoff G, Shibata A. Novel approaches to improve the efficacy of immuno-radiotherapy. Front Oncol 2019;9:156. https://doi.org/10.3389/fonc.2019.00156
  15. Zou W, Chen L. Inhibitory B7-family molecules in the tumour microenvironment. Nat Rev Immunol 2008;8:467-77. https://doi.org/10.1038/nri2326
  16. Pardoll DM. The blockade of immune checkpoints in cancer immunotherapy. Nat Rev Cancer 2012;12:252-64. https://doi.org/10.1038/nrc3239
  17. Deng L, Liang H, Burnette B, et al. Irradiation and anti-PD-L1 treatment synergistically promote antitumor immunity in mice. J Clin Invest 2014;124:687-95. https://doi.org/10.1172/JCI67313
  18. Dovedi SJ, Adlard AL, Lipowska-Bhalla G, et al. Acquired resistance to fractionated radiotherapy can be overcome by concurrent PD-L1 blockade. Cancer Res 2014;74:5458-68. https://doi.org/10.1158/0008-5472.CAN-14-1258
  19. Gong X, Li X, Jiang T, et al. Combined radiotherapy and anti-PD-L1 antibody synergistically enhances antitumor effect in non-small cell lung cancer. J Thorac Oncol 2017;12:1085-97. https://doi.org/10.1016/j.jtho.2017.04.014
  20. Twyman-Saint Victor C, Rech AJ, Maity A, et al. Radiation and dual checkpoint blockade activate non-redundant immune mechanisms in cancer. Nature 2015;520:373-7. https://doi.org/10.1038/nature14292
  21. Bauml JM, Mick R, Ciunci C, et al. Pembrolizumab after completion of locally ablative therapy for oligometastatic non-small cell lung cancer: a phase 2 trial. JAMA Oncol 2019;5:1283-90. https://doi.org/10.1001/jamaoncol.2019.1449
  22. Bozorgmehr F, Hommertgen A, Krisam J, et al. Fostering efficacy of anti-PD-1-treatment: nivolumab plus radiotherapy in advanced non-small cell lung cancer - study protocol of the FORCE trial. BMC Cancer 2019;19:1074. https://doi.org/10.1186/s12885-019-6205-0
  23. Kim HJ, Chang JS, Roh MR, et al. Effect of radiotherapy combined with pembrolizumab on local tumor control in mucosal melanoma patients. Front Oncol 2019;9:835. https://doi.org/10.3389/fonc.2019.00835
  24. Theelen WS, Peulen HM, Lalezari F, et al. Effect of pembrolizumab after stereotactic body radiotherapy vs pembrolizumab alone on tumor response in patients with advanced non-small cell lung cancer: results of the PEMBRO-RT phase 2 randomized clinical trial. JAMA Oncol 2019;5:1276-82. https://doi.org/10.1001/jamaoncol.2019.1478
  25. Yu JI, Lee SJ, Lee J, et al. Clinical significance of radiotherapy before and/or during nivolumab treatment in hepatocellular carcinoma. Cancer Med 2019;8:6986-94. https://doi.org/10.1002/cam4.2570
  26. Yilmaz MT, Elmali A, Yazici G. Abscopal effect, from myth to reality: from radiation oncologists' perspective. Cureus 2019;11:e3860.
  27. Weber R, Fleming V, Hu X, et al. Myeloid-derived suppressor cells hinder the anti-cancer activity of immune checkpoint inhibitors. Front Immunol 2018;9:1310. https://doi.org/10.3389/fimmu.2018.01310
  28. Chen HM, Ma G, Gildener-Leapman N, et al. Myeloid-derived suppressor cells as an immune parameter in patients with concurrent sunitinib and stereotactic body radiotherapy. Clin Cancer Res 2015;21:4073-85. https://doi.org/10.1158/1078-0432.CCR-14-2742
  29. Huang A, Zhang B, Wang B, Zhang F, Fan KX, Guo YJ. Increased CD14(+)HLA-DR (-/low) myeloid-derived suppressor cells correlate with extrathoracic metastasis and poor response to chemotherapy in non-small cell lung cancer patients. Cancer Immunol Immunother 2013;62:1439-51. https://doi.org/10.1007/s00262-013-1450-6
  30. Mengos AE, Gastineau DA, Gustafson MP. The CD14(+)HLA-DR(lo/neg) monocyte: an immunosuppressive phenotype that restrains responses to cancer immunotherapy. Front Immunol 2019;10:1147. https://doi.org/10.3389/fimmu.2019.01147
  31. Wang D, An G, Xie S, Yao Y, Feng G. The clinical and prognostic significance of CD14(+)HLA-DR(-/low) myeloid-derived suppressor cells in hepatocellular carcinoma patients receiving radiotherapy. Tumour Biol 2016;37:10427-33. https://doi.org/10.1007/s13277-016-4916-2
  32. Fleming V, Hu X, Weber R, et al. Targeting myeloid-derived suppressor cells to bypass tumor-induced immunosuppression. Front Immunol 2018;9:398. https://doi.org/10.3389/fimmu.2018.00398
  33. Gabrilovich DI, Bronte V, Chen SH, et al. The terminology issue for myeloid-derived suppressor cells. Cancer Res 2007;67:425. https://doi.org/10.1158/0008-5472.CAN-06-3037
  34. Bronte V, Brandau S, Chen SH, et al. Recommendations for myeloid-derived suppressor cell nomenclature and characterization standards. Nat Commun 2016;7:12150. https://doi.org/10.1038/ncomms12150
  35. Veglia F, Perego M, Gabrilovich D. Myeloid-derived suppressor cells coming of age. Nat Immunol 2018;19:108-19. https://doi.org/10.1038/s41590-017-0022-x
  36. Groth C, Hu X, Weber R, et al. Immunosuppression mediated by myeloid-derived suppressor cells (MDSCs) during tumour progression. Br J Cancer 2019;120:16-25. https://doi.org/10.1038/s41416-018-0333-1
  37. Rodriguez PC, Quiceno DG, Ochoa AC. L-arginine availability regulates T-lymphocyte cell-cycle progression. Blood 2007;109:1568-73. https://doi.org/10.1182/blood-2006-06-031856
  38. Goh CC, Roggerson KM, Lee HC, Golden-Mason L, Rosen HR, Hahn YS. Hepatitis C virus-induced myeloid-derived suppressor cells suppress NK cell $IFN-{\gamma}$ production by altering cellular metabolism via arginase-1. J Immunol 2016;196:2283-92. https://doi.org/10.4049/jimmunol.1501881
  39. Yu J, Du W, Yan F, et al. Myeloid-derived suppressor cells suppress antitumor immune responses through IDO expression and correlate with lymph node metastasis in patients with breast cancer. J Immunol 2013;190:3783-97. https://doi.org/10.4049/jimmunol.1201449
  40. Fallarino F, Grohmann U, You S, et al. The combined effects of tryptophan starvation and tryptophan catabolites down-regulate T cell receptor zeta-chain and induce a regulatory phenotype in naive T cells. J Immunol 2006;176:6752-61. https://doi.org/10.4049/jimmunol.176.11.6752
  41. Ohl K, Tenbrock K. Reactive oxygen species as regulators of MDSC-mediated immune suppression. Front Immunol 2018;9:2499. https://doi.org/10.3389/fimmu.2018.02499
  42. Noman MZ, Desantis G, Janji B, et al. PD-L1 is a novel direct target of HIF-$1{\alpha}$, and its blockade under hypoxia enhanced MDSC-mediated T cell activation. J Exp Med 2014;211:781-90. https://doi.org/10.1084/jem.20131916
  43. Tobin RP, Jordan KR, Robinson WA, et al. Targeting myeloid-derived suppressor cells using all-trans retinoic acid in melanoma patients treated with Ipilimumab. Int Immunopharmacol 2018;63:282-91. https://doi.org/10.1016/j.intimp.2018.08.007
  44. Huang ME, Ye YC, Chen SR, et al. Use of all-trans retinoic acid in the treatment of acute promyelocytic leukemia. Blood 1988;72:567-72. https://doi.org/10.1182/blood.v72.2.567.567
  45. Kusmartsev S, Su Z, Heiser A, et al. Reversal of myeloid cell-mediated immunosuppression in patients with metastatic renal cell carcinoma. Clin Cancer Res 2008;14:8270-8. https://doi.org/10.1158/1078-0432.CCR-08-0165
  46. Nefedova Y, Fishman M, Sherman S, Wang X, Beg AA, Gabrilovich DI. Mechanism of all-trans retinoic acid effect on tumor-associated myeloid-derived suppressor cells. Cancer Res 2007;67:11021-8. https://doi.org/10.1158/0008-5472.CAN-07-2593
  47. Schenk T, Stengel S, Zelent A. Unlocking the potential of retinoic acid in anticancer therapy. Br J Cancer 2014;111:2039-45. https://doi.org/10.1038/bjc.2014.412
  48. Iclozan C, Antonia S, Chiappori A, Chen DT, Gabrilovich D. Therapeutic regulation of myeloid-derived suppressor cells and immune response to cancer vaccine in patients with extensive stage small cell lung cancer. Cancer Immunol Immunother 2013;62:909-18. https://doi.org/10.1007/s00262-013-1396-8
  49. Mirza N, Fishman M, Fricke I, et al. All-trans-retinoic acid improves differentiation of myeloid cells and immune response in cancer patients. Cancer Res 2006;66:9299-307. https://doi.org/10.1158/0008-5472.can-06-1690
  50. Suzuki E, Kapoor V, Jassar AS, Kaiser LR, Albelda SM. Gemcitabine selectively eliminates splenic Gr-1+/CD11b+ myeloid suppressor cells in tumor-bearing animals and enhances antitumor immune activity. Clin Cancer Res 2005;11:6713-21. https://doi.org/10.1158/1078-0432.CCR-05-0883
  51. 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. Cancer Res 2010;70:3052-61. https://doi.org/10.1158/0008-5472.CAN-09-3690
  52. Eriksson E, Wenthe J, Irenaeus S, Loskog A, Ullenhag G. Gemcitabine reduces MDSCs, tregs and $TGF{\beta}-1$ while restoring the teff/treg ratio in patients with pancreatic cancer. J Transl Med 2016;14:282. https://doi.org/10.1186/s12967-016-1037-z
  53. Tavazoie MF, Pollack I, Tanqueco R, et al. LXR/ApoE activation restricts innate immune suppression in cancer. Cell 2018;172:825-40. https://doi.org/10.1016/j.cell.2017.12.026
  54. Le Tourneau C, Raymond E, Faivre S. Sunitinib: a novel tyrosine kinase inhibitor. A brief review of its therapeutic potential in the treatment of renal carcinoma and gastrointestinal stromal tumors (GIST). Ther Clin Risk Manag 2007;3:341-8. https://doi.org/10.2147/tcrm.2007.3.2.341
  55. Yang J, Yan J, Liu B. Targeting VEGF/VEGFR to modulate antitumor immunity. Front Immunol 2018;9:978. https://doi.org/10.3389/fimmu.2018.00978
  56. Ko JS, Zea AH, Rini BI, et al. Sunitinib mediates reversal of myeloid-derived suppressor cell accumulation in renal cell carcinoma patients. Clin Cancer Res 2009;15:2148-57. https://doi.org/10.1158/1078-0432.CCR-08-1332
  57. Karin N, Razon H. The role of CCR5 in directing the mobilization and biological function of CD11b(+)Gr1(+)Ly6C(low) polymorphonuclear myeloid cells in cancer. Cancer Immunol Immunother 2018;67:1949-53. https://doi.org/10.1007/s00262-018-2245-6
  58. Noel M, O'Reilly EM, Wolpin BM, et al. Phase 1b study of a small molecule antagonist of human chemokine (C-C motif) receptor 2 (PF-04136309) in combination with nab-paclitaxel/gemcitabine in first-line treatment of metastatic pancreatic ductal adenocarcinoma. Invest New Drugs 2019 Jul 12 [Epub]. https://doi.org/10.1007/s10637-019-00830-3.
  59. Blattner C, Fleming V, Weber R, et al. CCR5(+) myeloid-derived suppressor cells are enriched and activated in melanoma lesions. Cancer Res 2018;78:157-67. https://doi.org/10.1158/0008-5472.CAN-17-0348
  60. Hawila E, Razon H, Wildbaum G, et al. CCR5 directs the mobilization of CD11b(+)Gr1(+)Ly6C(low) polymorphonuclear myeloid cells from the bone marrow to the blood to support tumor development. Cell Rep 2017;21:2212-22. https://doi.org/10.1016/j.celrep.2017.10.104
  61. Jiao X, Nawab O, Patel T, et al. Recent advances targeting CCR5 for cancer and its role in immuno-oncology. Cancer Res 2019;79:4801-7. https://doi.org/10.1158/0008-5472.can-19-1167
  62. Highfill SL, Cui Y, Giles AJ, et al. Disruption of CXCR2-mediated MDSC tumor trafficking enhances anti-PD1 efficacy. Sci Transl Med 2014;6:237ra67. https://doi.org/10.1126/scitranslmed.3007974
  63. Sun L, Clavijo PE, Robbins Y, et al. Inhibiting myeloid-derived suppressor cell trafficking enhances T cell immunotherapy. JCI Insight 2019;4:e126853. https://doi.org/10.1172/jci.insight.126853
  64. Meyer C, Sevko A, Ramacher M, et al. Chronic inflammation promotes myeloid-derived suppressor cell activation blocking antitumor immunity in transgenic mouse melanoma model. Proc Natl Acad Sci U S A 2011;108:17111-6. https://doi.org/10.1073/pnas.1108121108
  65. Serafini P, Meckel K, Kelso M, et al. Phosphodiesterase-5 inhibition augments endogenous antitumor immunity by reducing myeloid-derived suppressor cell function. J Exp Med 2006;203:2691-702. https://doi.org/10.1084/jem.20061104
  66. Califano JA, Khan Z, Noonan KA, et al. Tadalafil augments tumor specific immunity in patients with head and neck squamous cell carcinoma. Clin Cancer Res 2015;21:30-8. https://doi.org/10.1158/1078-0432.CCR-14-1716
  67. Weed DT, Vella JL, Reis IM, et al. Tadalafil reduces myeloid-derived suppressor cells and regulatory T cells and promotes tumor immunity in patients with head and neck squamous cell carcinoma. Clin Cancer Res 2015;21:39-48. https://doi.org/10.1158/1078-0432.CCR-14-1711
  68. Shen L, Orillion A, Pili R. Histone deacetylase inhibitors as immunomodulators in cancer therapeutics. Epigenomics 2016;8:415-28. https://doi.org/10.2217/epi.15.118
  69. Christmas BJ, Rafie CI, Hopkins AC, et al. Entinostat converts immune-resistant breast and pancreatic cancers into checkpoint-responsive tumors by reprogramming tumor-infiltrating MDSCs. Cancer Immunol Res 2018;6:1561-77. https://doi.org/10.1158/2326-6066.CIR-18-0070
  70. Orillion A, Hashimoto A, Damayanti N, et al. Entinostat neutralizes myeloid-derived suppressor cells and enhances the antitumor effect of PD-1 inhibition in murine models of lung and renal cell carcinoma. Clin Cancer Res 2017;23:5187-201. https://doi.org/10.1158/1078-0432.CCR-17-0741
  71. Holmgaard RB, Zamarin D, Li Y, et al. Tumor-expressed IDO recruits and activates MDSCs in a treg-dependent manner. Cell Rep 2015;13:412-24. https://doi.org/10.1016/j.celrep.2015.08.077
  72. Zhu MMT, Dancsok AR, Nielsen TO. Indoleamine dioxygenase inhibitors: clinical rationale and current development. Curr Oncol Rep 2019;21:2. https://doi.org/10.1007/s11912-019-0750-1
  73. Ostrand-Rosenberg S, Horn LA, Ciavattone NG. Radiotherapy both promotes and inhibits myeloid-derived suppressor cell function: novel strategies for preventing the tumor-protective effects of radiotherapy. Front Oncol 2019;9:215. https://doi.org/10.3389/fonc.2019.00215
  74. Xu J, Escamilla J, Mok S, et al. CSF1R signaling blockade stanches tumor-infiltrating myeloid cells and improves the efficacy of radiotherapy in prostate cancer. Cancer Res 2013;73:2782-94. https://doi.org/10.1158/0008-5472.CAN-12-3981
  75. Kozin SV, Kamoun WS, Huang Y, Dawson MR, Jain RK, Duda DG. Recruitment of myeloid but not endothelial precursor cells facilitates tumor regrowth after local irradiation. Cancer Res 2010;0:5679-85.
  76. Kioi M, Vogel H, Schultz G, Hoffman RM, Harsh GR, Brown JM. Inhibition of vasculogenesis, but not angiogenesis, prevents the recurrence of glioblastoma after irradiation in mice. J Clin Invest 2010;120:694-705. https://doi.org/10.1172/JCI40283
  77. Susek KH, Karvouni M, Alici E, Lundqvist A. The role of CXC chemokine receptors 1-4 on immune cells in the tumor microenvironment. Front Immunol 2018;9:2159. https://doi.org/10.3389/fimmu.2018.02159
  78. Liang H, Deng L, Hou Y, et al. Host STING-dependent MDSC mobilization drives extrinsic radiation resistance. Nat Commun 2017;8:1736. https://doi.org/10.1038/s41467-017-01566-5
  79. Li A, Barsoumian HB, Schoenhals JE, et al. IDO1 inhibition overcomes radiation-induced "rebound immune suppression" by reducing numbers of IDO1-expressing myeloid-derived suppressor cells in the tumor microenvironment. Int J Radiat Oncol Biol Phys 2019;104:903-12. https://doi.org/10.1016/j.ijrobp.2019.03.022
  80. Filatenkov A, Baker J, Mueller AM, et al. Ablative tumor radiation can change the tumor immune cell microenvironment to induce durable complete remissions. Clin Cancer Res 2015;21:3727-39. https://doi.org/10.1158/1078-0432.CCR-14-2824
  81. Lan J, Li R, Yin LM, et al. Targeting myeloid-derived suppressor cells and programmed death ligand 1 confers therapeutic advantage of ablative hypofractionated radiation therapy compared with conventional fractionated radiation therapy. Int J Radiat Oncol Biol Phys 2018;101:74-87. https://doi.org/10.1016/j.ijrobp.2018.01.071
  82. Kao J, Chen CT, Tong CC, et al. Concurrent sunitinib and stereotactic body radiotherapy for patients with oligometastases: final report of a prospective clinical trial. Target Oncol 2014;9:145-53. https://doi.org/10.1007/s11523-013-0280-y
  83. Lin H, Wei S, Hurt EM, et al. Host expression of PD-L1 determines efficacy of PD-L1 pathway blockade-mediated tumor regression. J Clin Invest 2018;128:805-15. https://doi.org/10.1172/jci96113
  84. Tang H, Liang Y, Anders RA, et al. PD-L1 on host cells is essential for PD-L1 blockade-mediated tumor regression. J Clin Invest 2018;128:580-8. https://doi.org/10.1172/jci96061

Cited by

  1. Clinical Significance of Systemic Inflammation Markers in Newly Diagnosed, Previously Untreated Hepatocellular Carcinoma vol.12, pp.5, 2020, https://doi.org/10.3390/cancers12051300
  2. Cytokine Profiles of Non-Small Cell Lung Cancer Patients Treated with Concurrent Chemoradiotherapy with Regards to Radiation Pneumonitis Severity vol.10, pp.4, 2020, https://doi.org/10.3390/jcm10040699
  3. Radiation and Modulation of the Tumor Immune Microenvironment in Non–Small Cell Lung Cancer vol.31, pp.2, 2020, https://doi.org/10.1016/j.semradonc.2020.11.010
  4. Combined Radionuclide Therapy and Immunotherapy for Treatment of Triple Negative Breast Cancer vol.22, pp.9, 2020, https://doi.org/10.3390/ijms22094843
  5. Expansion of monocytic myeloid-derived suppressor cells ameliorated intestinal inflammatory response by radiation through SOCS3 expression vol.12, pp.9, 2021, https://doi.org/10.1038/s41419-021-04103-x
  6. Clinical importance of the absolute count of neutrophils, lymphocytes, monocytes, and platelets in newly diagnosed hepatocellular carcinoma vol.11, pp.1, 2020, https://doi.org/10.1038/s41598-021-82177-5