nach oben

Cancer Immunology, Immunotherapy

Erschienen in:

01.11.2014 | Original Article

Correlation between frequencies of blood monocytic myeloid-derived suppressor cells, regulatory T cells and negative prognostic markers in patients with castration-resistant metastatic prostate cancer

verfasst von: Manja Idorn, Tania Køllgaard, Per Kongsted, Lisa Sengeløv, Per thor Straten

Erschienen in: Cancer Immunology, Immunotherapy | Ausgabe 11/2014

Einloggen, um Zugang zu erhalten

Abstract

Myeloid-derived suppressor cells (MDSC) are believed to play a role in immune suppression and subsequent failure of T cells to mount an efficient anti-tumor response, by employing both direct T-cell inhibition as well as induction of regulatory T cells (Tregs). Investigating the frequency and function of immune suppressive cell subsets in the peripheral blood of 41 patients with prostate cancer (PC) and 36 healthy donors (HD) showed a significant increase in circulating CD14⁺ HLA-DR^low/neg monocytic MDSC (M-MDSC) and Tregs in patients with PC compared to HD. Furthermore, M-MDSC frequencies correlated positively with Treg levels. In vitro proliferation assay with autologous T cells confirmed M-MDSC-mediated T-cell suppression, and intracellular staining of immune suppressive enzyme iNOS revealed a higher expression in M-MDSC from patients with PC. Increased frequencies of M-MDSC correlated with known negative prognostic markers in patients with PC including elevated levels of lactate dehydrogenase and prostate-specific antigen. Accordingly, high levels of M-MDSC were associated with a shorter median overall survival. Our data strongly suggest that M-MDSC, possibly along with Tregs, play a role in establishing an immune suppressive environment in patients with PC. Moreover, correlation of M-MDSC frequency with known prognostic markers and the observed impact on OS could reflect a possible role in tumor progression. Further insight into the generation and function of MDSC and their interplay with Tregs and other cell types may suggest ways to tackle their induction and/or function to improve immunological tumor control.

Nur mit Berechtigung zugänglich

Klotz L, Zhang L, Lam A et al (2010) Clinical results of long-term follow-up of a large, active surveillance cohort with localized prostate cancer. J Clin Oncol 28:126–131. doi:10.1200/JCO.2009.24.2180 PubMedCrossRef

Carvalhal GF, Daudi SN, Kan D et al (2010) Correlation between serum prostate-specific antigen and cancer volume in prostate glands of different sizes. Urology 76:1072–1076. doi:10.1016/j.urology.2009.11.056 PubMedCrossRefPubMedCentral

Small EJ, Schellhammer PF, Higano CS et al (2006) Placebo-controlled phase III trial of immunologic therapy with sipuleucel-T (APC8015) in patients with metastatic, asymptomatic hormone refractory prostate cancer. J Clin Oncol 24:3089–3094. doi:10.1200/JCO.2005.04.5252 PubMedCrossRef

Kantoff PW, Schuetz TJ, Blumenstein Ba et al (2010) Overall survival analysis of a phase II randomized controlled trial of a Poxviral-based PSA-targeted immunotherapy in metastatic castration-resistant prostate cancer. J Clin Oncol 28:1099–1105. doi:10.1200/JCO.2009.25.0597 PubMedCrossRefPubMedCentral

Rigamonti N, Bellone M (2012) Prostate cancer, tumor immunity and a renewed sense of optimism in immunotherapy. Cancer Immunol Immunother 61:453–468. doi:10.1007/s00262-012-1216-6 PubMedCrossRef

Filipazzi P, Valenti R, Huber V et al (2007) Identification of a new subset of myeloid suppressor cells in peripheral blood of melanoma patients with modulation by a granulocyte-macrophage colony-stimulation factor-based antitumor vaccine. J Clin Oncol 25:2546–2553. doi:10.1200/JCO.2006.08.5829 PubMedCrossRef

Poschke I, Kiessling R (2012) On the armament and appearances of human myeloid-derived suppressor cells. Clin Immunol 144:250–268. doi:10.1016/j.clim.2012.06.003 PubMedCrossRef

Bronte V, Zanovello P (2005) Regulation of immune responses by l-arginine metabolism. Nat Rev Immunol 5:641–654. doi:10.1038/nri1668 PubMedCrossRef

Habibi D, Jalili RB, Forouzandeh F et al (2010) High expression of IMPACT protein promotes resistance to indoleamine 2,3-dioxygenase-induced cell death. J Cell Physiol 225:196–205. doi:10.1002/jcp.22220 PubMedCrossRef

10.

Gabrilovich DI, Nagaraj S (2009) Myeloid-derived suppressor cells as regulators of the immune system. Nat Rev Immunol 9:162–174. doi:10.1038/nri2506 PubMedCrossRefPubMedCentral

11.

Beyer M, Schultze JL (2006) Regulatory T cells in cancer. Blood 108:804–811. doi:10.1182/blood-2006-02-002774 PubMedCrossRef

12.

Gustafson MP, Lin Y, New KC et al (2010) Systemic immune suppression in glioblastoma: the interplay between CD14+ HLA-DRlo/neg monocytes, tumor factors, and dexamethasone. Neuro Oncol 12:631–644. doi:10.1093/neuonc/noq001 PubMedCrossRefPubMedCentral

13.

Kalathil S, Lugade Aa, Miller A et al (2013) Higher Frequencies of GARP+ CTLA-4+ Foxp3+ T regulatory cells and myeloid-derived suppressor cells in hepatocellular carcinoma patients are associated with impaired T-Cell functionality. Cancer Res 73:2435–2444. doi:10.1158/0008-5472.CAN-12-3381 PubMedCrossRefPubMedCentral

14.

Ko JS, Zea AH, Rini BI et al (2009) Sunitinib mediates reversal of myeloid-derived suppressor cell accumulation in renal cell carcinoma patients. Clin Cancer Res 15:2148–2157. doi:10.1158/1078-0432.CCR-08-1332 PubMedCrossRef

15.

Hoechst B, Gamrekelashvili J, Manns MP et al (2011) Plasticity of human Th17 cells and iTregs is orchestrated by different subsets of myeloid cells. Blood 117:6532–6541. doi:10.1182/blood-2010-11-317321 PubMedCrossRef

16.

Liu W, Putnam AL, Xu-Yu Z et al (2006) CD127 expression inversely correlates with FoxP3 and suppressive function of human CD4+ T reg cells. J Exp Med 203:1701–1711. doi:10.1084/jem.20060772 PubMedCrossRefPubMedCentral

17.

Riley CH, Jensen MK, Brimnes MK et al (2011) Increase in circulating CD4⁺CD25⁺Foxp3⁺ T cells in patients with Philadelphia-negative chronic myeloproliferative neoplasms during treatment with IFN-α. Blood 118:2170–2173. doi:10.1182/blood-2011-03-340992 PubMedCrossRef

18.

Halabi S, Lin C-Y, Kelly WK et al (2014) Updated prognostic model for predicting overall survival in first-line chemotherapy for patients with metastatic castration-resistant prostate cancer. J Clin Oncol 32:671–677. doi:10.1200/JCO.2013.52.3696 PubMedCrossRef

19.

Bronte V, Wang M, Overwijk WW et al (1998) Apoptotic death of CD8+ T lymphocytes after immunization: induction of a suppressive population of Mac-1+/Gr-1+ cells. J Immunol 161:5313–5320PubMedPubMedCentral

20.

Walter S, Weinschenk T, Stenzl A et al (2012) Multipeptide immune response to cancer vaccine IMA901 after single-dose cyclophosphamide associates with longer patient survival. Nat Med 18:1254–1261. doi:10.1038/nm.2883 PubMedCrossRef

21.

Vuk-Pavlović S, Bulur Pa, Lin Y et al (2010) Immunosuppressive CD14+ HLA-DRlow/- monocytes in prostate cancer. Prostate 70:443–455. doi:10.1002/pros.21078 PubMedPubMedCentral

22.

Brusa D, Simone M, Gontero P et al (2013) Circulating immunosuppressive cells of prostate cancer patients before and after radical prostatectomy: profile comparison. Int J Urol 20:971–978. doi:10.1111/iju PubMed

23.

Filipazzi P, Huber V, Rivoltini L (2012) Phenotype, function and clinical implications of myeloid-derived suppressor cells in cancer patients. Cancer Immunol Immunother 61:255–263. doi:10.1007/s00262-011-1161-9 PubMedCrossRef

24.

Kotsakis A, Harasymczuk M, Schilling B et al (2012) Myeloid-derived suppressor cell measurements in fresh and cryopreserved blood samples. J Immunol Methods 381:14–22. doi:10.1016/j.jim.2012.04.004 PubMedCrossRefPubMedCentral

25.

Poschke I, Mougiakakos D, Hansson J et al (2010) Immature immunosuppressive CD14+ HLA-DR-/low cells in melanoma patients are Stat3hi and overexpress CD80, CD83, and DC-sign. Cancer Res 70:4335–4345. doi:10.1158/0008-5472.CAN-09-3767 PubMedCrossRef

26.

Ramachandran IR, Martner A, Pisklakova A et al (2013) Myeloid-derived suppressor cells regulate growth of multiple myeloma by inhibiting T cells in bone marrow. J Immunol 190:3815–3823. doi:10.4049/jimmunol.1203373 PubMedCrossRefPubMedCentral

27.

Rodriguez PC, Zea AH, Culotta KS et al (2002) Regulation of T cell receptor CD3zeta chain expression by l-arginine. J Biol Chem 277:21123–21129. doi:10.1074/jbc.M110675200 PubMedCrossRef

28.

Whiteside TL (2004) Down-regulation of zeta-chain expression in T cells: a biomarker of prognosis in cancer? Cancer Immunol Immunother 53:865–878. doi:10.1007/s00262-004-0521-0 PubMed

29.

Bronte V, Kasic T, Gri G et al (2005) Boosting antitumor responses of T lymphocytes infiltrating human prostate cancers. J Exp Med 201:1257–1268. doi:10.1084/jem.20042028 PubMedCrossRefPubMedCentral

30.

Meidenbauer N, Gooding W, Spitler L, Harris D, Whiteside TL (2002) Recovery of zeta-chain expression and changes in spontaneous IL-10 production after PSA-based vaccines in patients with prostate cancer. Br J Cancer 86(2):168–178

31.

Afonso G, Scotto M, Renand A et al (2010) Critical parameters in blood processing for T-cell assays: validation on ELISpot and tetramer platforms. J Immunol Methods 359:28–36. doi:10.1016/j.jim.2010.05.005 PubMedCrossRef

32.

Derhovanessian E, Adams V, Hähnel K et al (2009) Pretreatment frequency of circulating IL-17+ CD4+ T-cells, but not Tregs, correlates with clinical response to whole-cell vaccination in prostate cancer patients. Int J Cancer 125:1372–1379. doi:10.1002/ijc.24497 PubMedCrossRef

33.

Nishikawa H, Sakaguchi S (2010) Regulatory T cells in tumor immunity. Int J Cancer 127:759–767. doi:10.1002/ijc.25429 PubMed

34.

Hoechst B, Ormandy LA, Ballmaier M et al (2008) A new population of myeloid-derived suppressor cells in hepatocellular carcinoma patients induces CD4(+)CD25(+)Foxp3(+) T cells. Gastroenterology 135:234–243. doi:10.1053/j.gastro.2008.03.020 PubMedCrossRef

35.

Mougiakakos D, Choudhury A, Lladser A et al (2010) Regulatory T cells in cancer. Adv Cancer Res 107:57–117. doi:10.1016/S0065-230X(10)07003-X PubMedCrossRef

36.

Gregg R, Smith CM, Clark FJ et al (2005) The number of human peripheral blood CD4+ CD25high regulatory T cells increases with age. Clin Exp Immunol 140:540–546. doi:10.1111/j.1365-2249.2005.02798.x PubMedCrossRefPubMedCentral

37.

Verschoor CP, Johnstone J, Millar J et al (2013) Blood CD33(+)HLA-DR(-) myeloid-derived suppressor cells are increased with age and a history of cancer. J Leukoc Biol 93:633–637. doi:10.1189/jlb.0912461 PubMedCrossRefPubMedCentral

38.

Yuan X-K, Zhao X-K, Xia Y-C et al (2011) Increased circulating immunosuppressive CD14+ HLA-DR-/low cells correlate with clinical cancer stage and pathological grade in patients with bladder carcinoma. J Int Med Res 39:1381–1391. doi:10.1177/147323001103900424 PubMedCrossRef

39.

Diaz-Montero CM, Salem ML, Nishimura MI et al (2009) Increased circulating myeloid-derived suppressor cells correlate with clinical cancer stage, metastatic tumor burden, and doxorubicin-cyclophosphamide chemotherapy. Cancer Immunol Immunother 58:49–59. doi:10.1007/s00262-008-0523-4 PubMedCrossRefPubMedCentral

40.

Arihara F, Mizukoshi E, Kitahara M et al (2013) Increase in CD14(+)HLA-DR (-/low) myeloid-derived suppressor cells in hepatocellular carcinoma patients and its impact on prognosis. Cancer Immunol Immunother 62:1421–1430. doi:10.1007/s00262-013-1447-1 PubMedCrossRef

41.

Azevedo A, Cunha V, Teixeira AL, Medeiros R (2011) IL-6/IL-6R as a potential key signaling pathway in prostate cancer development. World J Clin Oncol 2:384–396. doi:10.5306/wjco.v2.i12.384 PubMedCrossRefPubMedCentral

42.

Wu C-T, Hsieh C–C, Lin C–C et al (2012) Significance of IL-6 in the transition of hormone-resistant prostate cancer and the induction of myeloid-derived suppressor cells. J Mol Med 90:1343–1355. doi:10.1007/s00109-012-0916-x PubMedCrossRef

43.

Hori S, Nomura T, Sakaguchi S (2003) Control of regulatory T cell development by the transcription factor Foxp3. Science 299:1057–1061. doi:10.1126/science.1079490 PubMedCrossRef

44.

Kleinewietfeld M, Starke M, Di Mitri D et al (2009) CD49d provides access to “untouched” human Foxp3+ Treg free of contaminating effector cells. Blood 113:827–836. doi:10.1182/blood-2008-04-150524 PubMedCrossRef

45.

Weide B, Martens A, Zelba H et al (2014) Myeloid-derived suppressor cells predict survival of patients with advanced melanoma: comparison with regulatory T cells and NY-ESO-1- or Melan-A-specific T cells. Clin Cancer Res 20:1601–1609. doi:10.1158/1078-0432.CCR-13-2508 PubMedCrossRef

Titel: Correlation between frequencies of blood monocytic myeloid-derived suppressor cells, regulatory T cells and negative prognostic markers in patients with castration-resistant metastatic prostate cancer
verfasst von: Manja Idorn
Tania Køllgaard
Per Kongsted
Lisa Sengeløv
Per thor Straten
Publikationsdatum: 01.11.2014
Verlag: Springer Berlin Heidelberg
Erschienen in: Cancer Immunology, Immunotherapy / Ausgabe 11/2014
Print ISSN: 0340-7004
Elektronische ISSN: 1432-0851
DOI: https://doi.org/10.1007/s00262-014-1591-2

Neu im Fachgebiet Onkologie

Hodgkin Lymphom: BrECADD-Regime übertrifft die Erwartungen

05.06.2024 ASCO 2024 Kongressbericht

Das Kombinationsregime BrECADD mit Brentuximab vedotin ermöglichte in der Studie HD21 beim fortgeschrittenen klassischen Hodgkin-Lymphom eine unerwartet hohe progressionsfreie Überlebensrate von 94,3% nach vier Jahren. Gleichzeitig war das Regime besser tolerabel als der bisherige Standard eBEACOPP.

Antikörper-Drug-Konjugat verdoppelt PFS bei Multiplem Myelom

05.06.2024 ASCO 2024 Nachrichten

Zwei Phase-3-Studien deuten auf erhebliche Vorteile des Antikörper-Wirkstoff-Konjugats Belantamab-Mafodotin bei vorbehandelten Personen mit Multiplem Myelom: Im Vergleich mit einer Standard-Tripeltherapie wurde das progressionsfreie Überleben teilweise mehr als verdoppelt.

Neuer TKI gegen CML: Höhere Wirksamkeit, seltener Nebenwirkungen

05.06.2024 Chronische myeloische Leukämie Nachrichten

Der Tyrosinkinasehemmer (TKI) Asciminib ist älteren Vertretern dieser Gruppe bei CML offenbar überlegen: Personen mit frisch diagnostizierter CML entwickelten damit in einer Phase-3-Studie häufiger eine gut molekulare Response, aber seltener ernste Nebenwirkungen.

Brustkrebs-Prävention wird neu gedacht

04.06.2024 ASCO 2024 Kongressbericht

Zurzeit untersuchen Forschende verschiedene neue Ansätze zur Prävention von Brustkrebs bei Personen mit hohem Risiko. Darunter Denosumab, die prophylaktische Bestrahlung der Brust – und Impfungen.

Update Onkologie

Bestellen Sie unseren Fach-Newsletter und bleiben Sie gut informiert.

Newsletter bestellen

Springer Medizin

Abstract

Bitte loggen Sie sich ein, um Zugang zu diesem Inhalt zu erhalten

Weitere Artikel der Ausgabe 11/2014

FOXP3 and CTLA4 overexpression in multiple myeloma bone marrow as a sign of accumulation of CD4+ T regulatory cells

Mannose-Binding Lectin (MBL) and MBL-associated serine protease-2 (MASP-2) in women with malignant and benign ovarian tumours

Fast-growing in-transit melanoma metastasis after intratumoral interleukin-2

Erratum to: Immunological and biological changes during ipilimumab treatment and their potential correlation with clinical response and survival in patients with advanced melanoma