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Monocyte-derived dendritic cells reflect the immune functional status of a chromophobe renal cell carcinoma patient: Could it be a general phenomenon?

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Abstract

Purpose

The chromophobe renal cell carcinoma (ChRCC), though associated with a hereditary cancer syndrome, has a good prognosis after tumor removal. The lack of recurrence could be related to the absence of immune system compromise in patients or to an effective functional recovery of immune functions after tumor removal. Thus, we evaluated monocyte-derived dendritic cells (Mo-DCs) in a 34-year-old male who had a ChRCC, before and after tumor removal.

Methods

CD14+ monocytes from the patient’s peripheral blood, 1 week before and 3 months after partial nephrectomy, were differentiated in vitro into immature and mature Mo-DCs. These were harvested, analyzed by flow cytometry and used as stimulators of allogeneic T cells. Supernatants from cultures were collected for cytokine analysis.

Results

Tumor removal was associated with decreased expression of PD-L1, but also, surprisingly, of CD205, HLA-DR, CD80 and CD86 by Mo-DCs. Also, Mo-DC’s ability to stimulate T cell proliferation increased, along with IL-2Rα expression and IFN-γ production. Simultaneously, the patients’ Mo-DCs ability to induce Foxp3+ T cells decreased after surgery. One-year postoperative follow-up shows no tumor recurrence.

Conclusion

The presence of a ChRCC affected Mo-DCs generated in vitro, which recovered their function after tumor removal. This indicates that the favorable outcome observed after ChRCC resection may be due to the restoration of immunocompetence. Furthermore, since functional alterations described for DCs within tumors may be also found in Mo-DCs, their accurate functional analysis—not restricted to the determination of their surface immunophenotype—may provide an indirect “window” to the tumor microenvironment.

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Abbreviations

CFSE:

Carboxyfluorescein succinimidyl ester

ChRCC:

Chromophobe renal cell carcinoma

CT scan:

Computed axial tomography

Foxp3:

Forkhead box P3

FSC:

Forward scatter

GM-CSF:

Granulocyte macrophage colony-stimulating factor

IFN-γ:

Interferon gamma

DCs:

Dendritic cells

IL-2Rα:

Alpha chain of interleukin 2 receptor (CD25)

IL-4:

Interleukin 4

MFI:

Media fluorescence intensity

Mo-DCs:

Monocyte-derived dendritic cells

Mo-iDCs:

Monocyte-derived immature dendritic cells

Mo-mDCs:

Monocyte-derived mature dendritic cells

MRI:

Magnetic resonance imaging

NS Ctrl:

Non-stimulated control T cells

PBMCs:

Peripheral blood mononuclear cells

PD-L1:

Programmed cell death ligand 1

PHA:

Phytohaemagglutinin

SSC:

Side scatter

TNF-α:

Tumor necrosis factor alpha

References

  1. Burnet FM (1961) Immunological recognition of self. Science 133(3449):307–311

    Article  CAS  PubMed  Google Scholar 

  2. Schreiber RD, Old LJ, Smyth MJ (2011) Cancer immunoediting: integrating immunity’s roles in cancer suppression and promotion. Science 331(6024):1565–1570

    Article  CAS  PubMed  Google Scholar 

  3. Steinman RM (2012) Decisions about dendritic cells: past, present, and future. Annu Rev Immunol 30:1–22

    Article  CAS  PubMed  Google Scholar 

  4. Randolph GJ, Inaba K, Robbiani DF, Steinman RM, Muller WA (1999) Differentiation of phagocytic monocytes into lymph node dendritic cells in vivo. Immunity 11(6):753–761

    Article  CAS  PubMed  Google Scholar 

  5. Segura E, Touzot M, Bohineust A, Cappuccio A, Chiocchia G, Hosmalin A et al (2013) Human inflammatory dendritic cells induce Th17 cell differentiation. Immunity 38(2):336–348

    Article  CAS  PubMed  Google Scholar 

  6. Hawiger D, Inaba K, Dorsett Y, Guo M, Mahnke K, Rivera M et al (2001) Dendritic cells induce peripheral T cell unresponsiveness under steady state conditions in vivo. J Exp Med 194(6):769–779

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  7. Steinman RM, Banchereau J (2007) Taking dendritic cells into medicine. Nature 449(7161):419–426

    Article  CAS  PubMed  Google Scholar 

  8. Waldmann TA (2006) The biology of interleukin-2 and interleukin-15: implications for cancer therapy and vaccine design. Nat Rev Immunol 6(8):595–601

    Article  CAS  PubMed  Google Scholar 

  9. Dranoff G (2004) Cytokines in cancer pathogenesis and cancer therapy. Nat Rev Cancer 4(1):11–22

    Article  CAS  PubMed  Google Scholar 

  10. Baleeiro RB, Anselmo LB, Soares FA, Pinto CA, Ramos O, Gross JL et al (2008) High frequency of immature dendritic cells and altered in situ production of interleukin-4 and tumor necrosis factor-alpha in lung cancer. Cancer Immunol Immunother 57(9):1335–1345

    Article  CAS  PubMed  Google Scholar 

  11. Palucka K, Ueno H, Fay J, Banchereau J (2011) Dendritic cells and immunity against cancer. J Intern Med 269(1):64–73

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  12. Gabrilovich DI, Corak J, Ciernik IF, Kavanaugh D, Carbone DP (1997) Decreased antigen presentation by dendritic cells in patients with breast cancer. Clin Cancer Res 3(3):483–490

    CAS  PubMed  Google Scholar 

  13. Enk AH, Jonuleit H, Saloga J, Knop J (1997) Dendritic cells as mediators of tumor-induced tolerance in metastatic melanoma. Int J Cancer 73(3):309–316

    Article  CAS  PubMed  Google Scholar 

  14. Della Bella S, Gennaro M, Vaccari M, Ferraris C, Nicola S, Riva A et al (2003) Altered maturation of peripheral blood dendritic cells in patients with breast cancer. Br J Cancer 89(8):1463–1472

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  15. Walker SR, Ogagan PD, DeAlmeida D, Aboka AM, Barksdale EM Jr (2006) Neuroblastoma impairs chemokine-mediated dendritic cell migration in vitro. J Pediatr Surg 41(1):260–265

    Article  PubMed  Google Scholar 

  16. Ramos RN, Chin LS, Dos Santos AP, Bergami-Santos PC, Laginha F, Barbuto JA (2012) Monocyte-derived dendritic cells from breast cancer patients are biased to induce CD4 + CD25 + Foxp3 + regulatory T cells. J Leukoc Biol 92(3):673–682

    Article  CAS  PubMed  Google Scholar 

  17. Wang L, Pino-Lagos K, de Vries VC, Guleria I, Sayegh MH, Noelle RJ (2008) Programmed death 1 ligand signaling regulates the generation of adaptive Foxp3 + CD4 + regulatory T cells. Proc Natl Acad Sci USA 105(27):9331–9336

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  18. Francisco LM, Salinas VH, Brown KE, Vanguri VK, Freeman GJ, Kuchroo VK et al (2009) PD-L1 regulates the development, maintenance, and function of induced regulatory T cells. J Exp Med 206(13):3015–3029

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  19. Staveley-O’Carroll K, Sotomayor E, Montgomery J, Borrello I, Hwang L, Fein S et al (1998) Induction of antigen-specific T cell anergy: an early event in the course of tumor progression. Proc Natl Acad Sci USA 95(3):1178–1183

    Article  PubMed Central  PubMed  Google Scholar 

  20. Zou W (2006) Regulatory T cells, tumour immunity and immunotherapy. Nat Rev Immunol 6(4):295–307

    Article  CAS  PubMed  Google Scholar 

  21. Curiel TJ (2008) Regulatory T cells and treatment of cancer. Curr Opin Immunol 20(2):241–246

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  22. Crespo J, Sun H, Welling TH, Tian Z, Zou W (2013) T cell anergy, exhaustion, senescence, and stemness in the tumor microenvironment. Curr Opin Immunol 25(2):214–221

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  23. Stec R, Grala B, Maczewski M, Bodnar L, Szczylik C (2009) Chromophobe renal cell cancer—review of the literature and potential methods of treating metastatic disease. J Exp Clin Cancer Res 28:134

    Article  PubMed Central  PubMed  Google Scholar 

  24. Singer EA, Bratslavsky G, Linehan WM, Srinivasan R (2010) Targeted therapies for non-clear renal cell carcinoma. Target Oncol 5(2):119–129

    Article  PubMed Central  PubMed  Google Scholar 

  25. Vera-Badillo FE, Conde E, Duran I (2012) Chromophobe renal cell carcinoma: a review of an uncommon entity. Int J Urol 19(10):894–900

    Article  CAS  PubMed  Google Scholar 

  26. Sallusto F, Lanzavecchia A (1994) Efficient presentation of soluble antigen by cultured human dendritic cells is maintained by granulocyte/macrophage colony-stimulating factor plus interleukin 4 and downregulated by tumor necrosis factor alpha. J Exp Med 179(4):1109–1118

    Article  CAS  PubMed  Google Scholar 

  27. Neron S, Thibault L, Dussault N, Cote G, Ducas E, Pineault N et al (2007) Characterization of mononuclear cells remaining in the leukoreduction system chambers of apheresis instruments after routine platelet collection: a new source of viable human blood cells. Transfusion 47(6):1042–1049

    Article  PubMed  Google Scholar 

  28. Barbuto JA (2013) Are dysfunctional monocyte-derived dendritic cells in cancer an explanation for cancer vaccine failures? Immunotherapy 5(2):105–107

    Article  CAS  PubMed  Google Scholar 

  29. Shih VF, Davis-Turak J, Macal M, Huang JQ, Ponomarenko J, Kearns JD et al (2012) Control of RelB during dendritic cell activation integrates canonical and noncanonical NF-kappaB pathways. Nat Immunol 13(12):1162–1170

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  30. Lutz MB, Schuler G (2002) Immature, semi-mature and fully mature dendritic cells: which signals induce tolerance or immunity? Trends Immunol 23(9):445–449

    Article  CAS  PubMed  Google Scholar 

  31. Jiang W, Swiggard WJ, Heufler C, Peng M, Mirza A, Steinman RM et al (1995) The receptor DEC-205 expressed by dendritic cells and thymic epithelial cells is involved in antigen processing. Nature 375(6527):151–155

    Article  CAS  PubMed  Google Scholar 

  32. Mahnke K, Qian Y, Fondel S, Brueck J, Becker C, Enk AH (2005) Targeting of antigens to activated dendritic cells in vivo cures metastatic melanoma in mice. Cancer Res 65(15):7007–7012

    Article  CAS  PubMed  Google Scholar 

  33. Flacher V, Sparber F, Tripp CH, Romani N, Stoitzner P (2009) Targeting of epidermal Langerhans cells with antigenic proteins: attempts to harness their properties for immunotherapy. Cancer Immunol Immunother 58(7):1137–1147

    Article  CAS  PubMed  Google Scholar 

  34. Birkholz K, Schwenkert M, Kellner C, Gross S, Fey G, Schuler-Thurner B et al (2010) Targeting of DEC-205 on human dendritic cells results in efficient MHC class II-restricted antigen presentation. Blood 116(13):2277–2285

    Article  CAS  PubMed  Google Scholar 

  35. Bonifaz LC, Bonnyay DP, Charalambous A, Darguste DI, Fujii S, Soares H et al (2004) In vivo targeting of antigens to maturing dendritic cells via the DEC-205 receptor improves T cell vaccination. J Exp Med 199(6):815–824

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  36. Shah W, Yan X, Jing L, Zhou Y, Chen H, Wang Y (2011) A reversed CD4/CD8 ratio of tumor-infiltrating lymphocytes and a high percentage of CD4(+)FOXP3(+) regulatory T cells are significantly associated with clinical outcome in squamous cell carcinoma of the cervix. Cell Mol Immunol 8(1):59–66

    Article  PubMed Central  PubMed  Google Scholar 

  37. Ridgway W, Fasso M, Fathman CG (1998) Following antigen challenge, T cells up-regulate cell surface expression of CD4 in vitro and in vivo. J Immunol 161(2):714–720

    CAS  PubMed  Google Scholar 

  38. Gasocyne RD, Whitney RB, Levy JG (1978) Recovery of immune competence after tumour resection in mice: correlation with loss of suppressor elements. Br J Cancer 37(2):190–198

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  39. Lombardi G, Sidhu S, Batchelor R, Lechler R (1994) Anergic T cells as suppressor cells in vitro. Science 264(5165):1587–1589

    Article  CAS  PubMed  Google Scholar 

  40. Sheu BC, Hsu SM, Ho HN, Lin RH, Torng PL, Huang SC (1999) Reversed CD4/CD8 ratios of tumor-infiltrating lymphocytes are correlated with the progression of human cervical carcinoma. Cancer 86(8):1537–1543

    Article  CAS  PubMed  Google Scholar 

  41. Nakano O, Sato M, Naito Y, Suzuki K, Orikasa S, Aizawa M et al (2001) Proliferative activity of intratumoral CD8(+) T-lymphocytes as a prognostic factor in human renal cell carcinoma: clinicopathologic demonstration of antitumor immunity. Cancer Res 61(13):5132–5136

    CAS  PubMed  Google Scholar 

  42. Grabenbauer GG, Lahmer G, Distel L, Niedobitek G (2006) Tumor-infiltrating cytotoxic T cells but not regulatory T cells predict outcome in anal squamous cell carcinoma. Clin Cancer Res 12(11 Pt 1):3355–3360

    Article  CAS  PubMed  Google Scholar 

  43. Amadori A, Zamarchi R, De Silvestro G, Forza G, Cavatton G, Danieli GA et al (1995) Genetic control of the CD4/CD8 T-cell ratio in humans. Nat Med 1(12):1279–1283

    Article  CAS  PubMed  Google Scholar 

  44. Kiniwa Y, Miyahara Y, Wang HY, Peng W, Peng G, Wheeler TM et al (2007) CD8 + Foxp3 + regulatory T cells mediate immunosuppression in prostate cancer. Clin Cancer Res 13(23):6947–6958

    Article  CAS  PubMed  Google Scholar 

  45. Chaput N, Louafi S, Bardier A, Charlotte F, Vaillant JC, Menegaux F et al (2009) Identification of CD8 + CD25 + Foxp3 + suppressive T cells in colorectal cancer tissue. Gut 58(4):520–529

    Article  CAS  PubMed  Google Scholar 

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Acknowledgments

This work was supported by grants from Fundação de Amparo à Pesquisa do Estado de São Paulo, FAPESP (2009/54599-5, 2011/05331-0 and 2012/23478-0) and Conselho Nacional de Desenvolvimento Científico e Tecnológico—CNPq. We thank Instituto HOC—Hospital Alemão Oswaldo Cruz, São Paulo—Brazil and Dr. Adilson Kleber Ferreira for the critical reading of this manuscript. This work is dedicated to the patient.

Conflict of interest

The authors declare no financial or other conflict.

Ethical standard

Blood samples and images were collected after written informed consent signed by the patient and the healthy donors, who agreed with the publication of this case report.

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Authors and Affiliations

  1. Laboratory of Tumor Immunology, Department of Immunology, Institute of Biomedical Sciences, University of Sao Paulo, Av. Prof. Lineu Prestes, 1730, São Paulo, SP, CEP 05508-900, Brazil

    Maria A. Clavijo-Salomon, Rodrigo N. Ramos, Celia R. Pizzo, Patricia C. Bergami-Santos & Jose Alexandre M. Barbuto

  2. Section of Uro-Oncology of the São Paulo State Cancer Institute - ICESP, Division of Urology, University of São Paulo Medical School, São Paulo, SP, Brazil

    Alexandre Crippa

  3. Cell and Molecular Therapy Center NUCEL-NETCEM, University of Sao Paulo, Sao Paulo, Brazil

    Jose Alexandre M. Barbuto

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  1. Maria A. Clavijo-Salomon
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Correspondence to Jose Alexandre M. Barbuto.

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Clavijo-Salomon, M.A., Ramos, R.N., Crippa, A. et al. Monocyte-derived dendritic cells reflect the immune functional status of a chromophobe renal cell carcinoma patient: Could it be a general phenomenon?. Cancer Immunol Immunother 64, 161–171 (2015). https://doi.org/10.1007/s00262-014-1625-9

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