Tumor-infiltrating and circulating granulocytic myeloid-derived suppressor cells correlate with disease activity and adverse clinical outcomes in mycosis fungoides
Cutaneous T cell lymphomas (CTCL) are rare and histologically diverse lymphoproliferative neoplasms, with mycosis fungoides (MF) representing the most common disease subset. Given the emerging role of myeloid-derived suppressor cells (MDSC) as a clinically applicable biomarker in solid tumors, we sought to investigate the presence of tumor-infiltrating and circulating MDSC in early- and advanced-stage MF patients and evaluate their prognostic significance in patient overall survival.
Tumor-infiltrating MDSC were assessed immunohistochemically with Arginase-1 in 31 MF and 14 non-MF skin punch biopsies. Circulating MDSC were assessed with flow cytometry in freshly isolated PBMC from 29 MF patients. Granulocytic MDSC (G-MDSC) were defined as CD11b+CD14−CD15+ and monocytic MDSC (M-MDSC) were defined as CD11b+CD14+HLA-DRlow/-.
MDSC infiltration occurred in approximately one-third (35.5%) of CTCL lesions, with a predilection for non-MF lesions (p < 0.05). The predominant morphology of MDSC was granulocytic. Although in MF lesions the presence of MDSC infiltrates did not correlate with clinical stage, it conferred significantly worse overall survival outcomes (p < 0.05). Circulating G-MDSC were significantly higher in MF patients compared to healthy donor controls (p < 0.0001), while M-MDSC did not show any statistically significant difference. G-MDSC were significantly higher in patients with active disease compared to patients who were in partial remission (p < 0.01). As with tumor-infiltrating MDSC, clinical stage did not correlate with circulating G-MDSC levels, while prospective overall survival analysis showed that patients with high levels of circulating G-MDSC have significantly inferior outcomes (p < 0.01).
This study shows that G-MDSC could represent a novel and easily assessable biomarker in MF, which mirrors disease activity and can predict patient subgroups with aggressive clinical features.
KeywordsCutaneous T-cell Lymphoma Mycosis fungoides Myeloid-derived suppressor cells
We would like to thank Dr. Katya Manova and the personnel of the Molecular Cytology Core Facility at Memorial Sloan Kettering Cancer Center, as well as the Pathology Core Facility for the help with immunohistochemistry studies.
KVA, SP, CB, MLP and MS conceived and designed the experiments. KVA and SP performed the experiments. KVA and MP evaluated H&E morphology and analyzed the immunohistochemistry data. KVA and SP performed the flow cytometry analysis and statistical analysis. PK, MA, MLP and MS helped in the collection of patient material. KVA wrote the manuscript. MLP and MS reviewed and edited the manuscript.
This work was supported by The Lymphoma Foundation, the Greenberg Lymphoma Research Award (MSKCC) and the P30 CA008748 MSK Cancer Center Support Grant/Core Grant.
Compliance with ethical standards
Conflict of interest
M.Lia Palomba serves as a consultant for Merck and Pharmcyclics. The rest of the authors have no interest to disclose.
Research involving human participants
Specimen collection was approved by the Memorial Sloan Kettering Cancer Center Institutional Review Board and the National and Kapodistrian University of Athens Bioethics committee.
Patient material was obtained from patients who had previously signed informed consent, in accordance with the Declaration of Helsinki.
- 1.Swerdlow SH CE, Harris NL et al (2017) WHO classification of tumours of haematopoietic and lymphoid tissues. 4th edn. International Agency for Research on Cancer (IARC), LyonGoogle Scholar
- 2.Swerdlow SH, Campo E, Pileri SA, Harris NL, Stein H, Siebert R, Advani R, Ghielmini M, Salles GA, Zelenetz AD, Jaffe ES. The 2016 revision of the World Health Organization classification of lymphoid neoplasms. Blood. 2016;127(20):2375–90. https://doi.org/10.1182/blood-2016-01-643569.CrossRefPubMedPubMedCentralGoogle Scholar
- 3.Choi J, Goh G, Walradt T, Hong BS, Bunick CG, Chen K, Bjornson RD, Maman Y, Wang T, Tordoff J, Carlson K, Overton JD, Liu KJ, Lewis JM, Devine L, Barbarotta L, Foss FM, Subtil A, Vonderheid EC, Edelson RL, Schatz DG, Boggon TJ, Girardi M, Lifton RP. Genomic landscape of cutaneous T cell lymphoma. Nat Genet. 2015;47(9):1011–9. https://doi.org/10.1038/ng.3356.CrossRefPubMedPubMedCentralGoogle Scholar
- 4.da Silva Almeida AC, Abate F, Khiabanian H, Martinez-Escala E, Guitart J, Tensen CP, Vermeer MH, Rabadan R, Ferrando A, Palomero T. The mutational landscape of cutaneous T cell lymphoma and Sezary syndrome. Nat Genet. 2015;47(12):1465–70. https://doi.org/10.1038/ng.3442.CrossRefPubMedPubMedCentralGoogle Scholar
- 5.Park J, Yang J, Wenzel AT, Ramachandran A, Lee WJ, Daniels JC, Kim J, Martinez-Escala E, Amankulor N, Pro B, Guitart J, Mendillo ML, Savas JN, Boggon TJ, Choi J (2017) Genomic analysis of 220 CTCLs identifies a novel recurrent gain-of-function alteration in RLTPR (p.Q575E). Blood 130(12):1430–1440. https://doi.org/10.1182/blood-2017-02-768234 CrossRefGoogle Scholar
- 6.Vaque JP, Gomez-Lopez G, Monsalvez V, Varela I, Martinez N, Perez C, Dominguez O, Grana O, Rodriguez-Peralto JL, Rodriguez-Pinilla SM, Gonzalez-Vela C, Rubio-Camarillo M, Martin-Sanchez E, Pisano DG, Papadavid E, Papadaki T, Requena L, Garcia-Marco JA, Mendez M, Provencio M, Hospital M, Suarez-Massa D, Postigo C, San Segundo D, Lopez-Hoyos M, Ortiz-Romero PL, Piris MA, Sanchez-Beato M. PLCG1 mutations in cutaneous T-cell lymphomas. Blood. 2014;123(13):2034–43. https://doi.org/10.1182/blood-2013-05-504308.CrossRefPubMedGoogle Scholar
- 7.Kiel MJ, Sahasrabuddhe AA, Rolland DC, Velusamy T, Chung F, Schaller M, Bailey NG, Betz BL, Miranda RN, Porcu P, Byrd JC, Medeiros LJ, Kunkel SL, Bahler DW, Lim MS, Elenitoba-Johnson KS. Genomic analyses reveal recurrent mutations in epigenetic modifiers and the JAK-STAT pathway in Sezary syndrome. Nat Commun. 2015;6:8470. https://doi.org/10.1038/ncomms9470.CrossRefPubMedPubMedCentralGoogle Scholar
- 8.Guenova E, Watanabe R, Teague JE, Desimone JA, Jiang Y, Dowlatshahi M, Schlapbach C, Schaekel K, Rook AH, Tawa M, Fisher DC, Kupper TS, Clark RA. TH2 cytokines from malignant cells suppress TH1 responses and enforce a global TH2 bias in leukemic cutaneous T-cell lymphoma. Clin Cancer Res. 2013;19(14):3755–63. https://doi.org/10.1158/1078-0432.CCR-12-3488.CrossRefPubMedPubMedCentralGoogle Scholar
- 9.Nakajima R, Miyagaki T, Hirakawa M, Oka T, Takahashi N, Suga H, Yoshizaki A, Fujita H, Asano Y, Sugaya M, Sato S. Interleukin-25 is involved in cutaneous T-cell lymphoma progression by establishing a T helper 2-dominant microenvironment. Br J Dermatol. 2018;178(6):1373–82. https://doi.org/10.1111/bjd.16237.CrossRefPubMedGoogle Scholar
- 15.Sun HL, Zhou X, Xue YF, Wang K, Shen YF, Mao JJ, Guo HF, Miao ZN. Increased frequency and clinical significance of myeloid-derived suppressor cells in human colorectal carcinoma. World J Gastroenterol. 2012;18(25):3303–9. https://doi.org/10.3748/wjg.v18.i25.3303.CrossRefPubMedPubMedCentralGoogle Scholar
- 16.Diaz-Montero CM, Salem ML, Nishimura MI, Garrett-Mayer E, Cole DJ, Montero AJ. Increased circulating myeloid-derived suppressor cells correlate with clinical cancer stage, metastatic tumor burden, and doxorubicin-cyclophosphamide chemotherapy. Cancer Immunol Immunother. 2009;58(1):49–59. https://doi.org/10.1007/s00262-008-0523-4.CrossRefPubMedGoogle Scholar
- 17.Yang G, Shen W, Zhang Y, Liu M, Zhang L, Liu Q, Lu HH, Bo J. Accumulation of myeloid-derived suppressor cells (MDSCs) induced by low levels of IL-6 correlates with poor prognosis in bladder cancer. Oncotarget. 2017;8(24):38378–88. https://doi.org/10.18632/oncotarget.16386.CrossRefPubMedPubMedCentralGoogle Scholar
- 18.Jordan KR, Amaria RN, Ramirez O, Callihan EB, Gao D, Borakove M, Manthey E, Borges VF, McCarter MD. Myeloid-derived suppressor cells are associated with disease progression and decreased overall survival in advanced-stage melanoma patients. Cancer Immunol Immunother. 2013;62(11):1711–22. https://doi.org/10.1007/s00262-013-1475-x.CrossRefPubMedPubMedCentralGoogle Scholar
- 20.Wu L, Liu H, Guo H, Wu Q, Yu S, Qin Y, Wang G, Wu Q, Zhang R, Wang L, Zhang L, Liu C, Jiao S, Liu T. Circulating and tumor-infiltrating myeloid-derived suppressor cells in cervical carcinoma patients. Oncol Lett. 2018;15(6):9507–15. https://doi.org/10.3892/ol.2018.8532.CrossRefPubMedPubMedCentralGoogle Scholar
- 21.Wang Z, Zhang L, Wang H, Xiong S, Li Y, Tao Q, Xiao W, Qin H, Wang Y, Zhai Z. Tumor-induced CD14+HLA-DR (-/low) myeloid-derived suppressor cells correlate with tumor progression and outcome of therapy in multiple myeloma patients. Cancer Immunol Immunother. 2015;64(3):389–99. https://doi.org/10.1007/s00262-014-1646-4.CrossRefPubMedGoogle Scholar
- 22.Wu C, Wu X, Zhang X, Chai Y, Guo Q, Li L, Yue L, Bai J, Wang Z, Zhang L. Prognostic significance of peripheral monocytic myeloid-derived suppressor cells and monocytes in patients newly diagnosed with diffuse large b-cell lymphoma. Int J Clin Exp Med. 2015;8(9):15173–81.PubMedPubMedCentralGoogle Scholar
- 23.Gorgun GT, Whitehill G, Anderson JL, Hideshima T, Maguire C, Laubach J, Raje N, Munshi NC, Richardson PG, Anderson KC. Tumor-promoting immune-suppressive myeloid-derived suppressor cells in the multiple myeloma microenvironment in humans. Blood. 2013;121(15):2975–87. https://doi.org/10.1182/blood-2012-08-448548.CrossRefPubMedPubMedCentralGoogle Scholar
- 24.Pileri A, Agostinelli C, Sessa M, Quaglino P, Santucci M, Tomasini C, Grandi V, Fava P, Astrua C, Righi S, Patrizi A, Pileri SA, Pimpinelli N. Langerhans, plasmacytoid dendritic and myeloid-derived suppressor cell levels in mycosis fungoides vary according to the stage of the disease. Virchows Arch. 2017;470(5):575–82. https://doi.org/10.1007/s00428-017-2107-1.CrossRefPubMedGoogle Scholar
- 25.Geskin LJ, Akilov OE, Kwon S, Schowalter M, Watkins S, Whiteside TL, Butterfield LH, Falo LD Jr. Therapeutic reduction of cell-mediated immunosuppression in mycosis fungoides and Sezary syndrome. Cancer Immunol Immunother. 2018;67(3):423–34. https://doi.org/10.1007/s00262-017-2090-z.CrossRefPubMedGoogle Scholar
- 27.Wang T, Feldman AL, Wada DA, Lu Y, Polk A, Briski R, Ristow K, Habermann TM, Thomas D, Ziesmer SC, Wellik LE, Lanigan TM, Witzig TE, Pittelkow MR, Bailey NG, Hristov AC, Lim MS, Ansell SM, Wilcox RA. GATA-3 expression identifies a high-risk subset of PTCL, NOS with distinct molecular and clinical features. Blood. 2014;123(19):3007–155. https://doi.org/10.1182/blood-2013-12-544809.CrossRefPubMedPubMedCentralGoogle Scholar