Skip to main content

Advertisement

SpringerLink
Log in

Tumor Infiltrating Mast Cells (TIMs) Confers a Marked Survival Advantage in Nonmetastatic Clear-Cell Renal Cell Carcinoma

  • Urologic Oncology
  • Published:
Annals of Surgical Oncology Aims and scope Submit manuscript

Abstract

Purpose

The role played by the innate immune system in determining the clinical outcome of clear-cell renal cell carcinoma (ccRCC) was still blurred. This study was designed to investigate the prognostic significance of tumor infiltrating mast cells (TIMs) in ccRCC.

Methods

The study retrospectively enrolled a training set (474 patients) and a validation set (188 patients) with nonmetastasis (pT1-4N0M0) ccRCC from two institutional medical centers of China. TIMs was evaluated by immunohistochemical staining of tryptase and its association with clinicopathologic features and prognosis were evaluated.

Results

In ccRCC tissues, TIMs ranged from 0 to 103 cells/mm2 and 0 to 113 cells/mm2 in the training set and validation set, respectively. TIMs was negatively correlated with tumor size (P < 0.001 and P < 0.001, respectively), pathological T stage (P = 0.005 and P = 0.007, respectively) and Fuhrman grade (P < 0.001 and P < 0.001, respectively). Patients with abundant TIMs infiltration showed significantly longer cancer-specific survival in the training cohort and the validation cohort (P < 0.001 and P < 0.001). Patients with abundant mast cell infiltration showed significantly longer overall survival in the TCGA cohort (P < 0.001). Moreover, multivariate analysis identified TIMs as an independent prognostic factor for cancer-specific survival (CSS) and relapse-free survival (RFS). Also, TIMs was significantly correlated with CSS and RFS of the mediate and high-risk patients in the training cohort and the validation cohort.

Conclusions

TIMs density is a powerful independent prognostic factor for CSS and RFS in patients with nonmetastasis (pT1-4N0M0) ccRCC.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

References

  1. Yang JC, Childs R. Immunotherapy for renal cell cancer. J Clin Oncol. 2006;24(35):5576–83.

    Article  CAS  PubMed  Google Scholar 

  2. Ljungberg B, Bensalah K, Canfield S, et al. EAU guidelines on renal cell carcinoma: 2014 update. Eur Urol. 2015;67(5):913–24.

    Article  PubMed  Google Scholar 

  3. Motzer RJ, Agarwal N, Beard C, et al. NCCN clinical practice guidelines in oncology: kidney cancer. J Natl Compr Cancer Netw JNCCN. 2009;7(6):618–30.

    CAS  Google Scholar 

  4. Inman BA, Harrison MR, George DJ. Novel immunotherapeutic strategies in development for renal cell carcinoma. Eur Urol. 2013;63(5):881–9.

    Article  PubMed  Google Scholar 

  5. Rosenberg SA, Lotze MT, Yang JC, et al. Prospective randomized trial of high-dose interleukin-2 alone or in conjunction with lymphokine-activated killer cells for the treatment of patients with advanced cancer. J Natl Cancer Inst. 1993;85(8):622–32.

    Article  CAS  PubMed  Google Scholar 

  6. Motzer RJ, Escudier B, McDermott DF, et al. Nivolumab versus everolimus in advanced renal-cell carcinoma. N Engl J Med. 2015;373(19):1803–13.

    Article  CAS  PubMed  Google Scholar 

  7. Dimitriadou V, Koutsilieris M. Mast cell-tumor cell interactions: for or against tumour growth and metastasis? Anticancer Res. 1997;17(3A):1541–9.

    CAS  PubMed  Google Scholar 

  8. Beer TW, Ng LB, Murray K. Mast cells have prognostic value in Merkel cell carcinoma. Am J Dermatopathol. 2008;30(1):27–30.

    Article  PubMed  Google Scholar 

  9. Giusca SE, Caruntu ID, Cimpean AM, et al. Tryptase-positive and CD117 positive mast cells correlate with survival in patients with liver metastasis. Anticancer Res. 2015;35(10):5325–31.

    CAS  PubMed  Google Scholar 

  10. Ju MJ, Qiu SJ, Gao Q, et al. Combination of peritumoral mast cells and T-regulatory cells predicts prognosis of hepatocellular carcinoma. Cancer Sci. 2009;100(7):1267–74.

    Article  CAS  PubMed  Google Scholar 

  11. Nonomura N, Takayama H, Nishimura K, et al. Decreased number of mast cells infiltrating into needle biopsy specimens leads to a better prognosis of prostate cancer. Br J Cancer. 2007;97(7):952–6.

    CAS  PubMed  PubMed Central  Google Scholar 

  12. Ogino S, Shima K, Baba Y, et al. Colorectal cancer expression of peroxisome proliferator-activated receptor gamma (PPARG, PPARgamma) is associated with good prognosis. Gastroenterology. 2009;136(4):1242–50.

    Article  CAS  PubMed  Google Scholar 

  13. Strouch MJ, Cheon EC, Salabat MR, et al. Crosstalk between mast cells and pancreatic cancer cells contributes to pancreatic tumor progression. Clin Cancer Res. 2010;16(8):2257–65.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Welsh TJ, Green RH, Richardson D, Waller DA, O’Byrne KJ, Bradding P. Macrophage and mast-cell invasion of tumor cell islets confers a marked survival advantage in non-small-cell lung cancer. J Clin Oncol. 2005;23(35):8959–67.

    Article  PubMed  Google Scholar 

  15. Taskinen M, Karjalainen-Lindsberg ML, Leppa S. Prognostic influence of tumor-infiltrating mast cells in patients with follicular lymphoma treated with rituximab and CHOP. Blood. 2008;111(9):4664–7.

    Article  CAS  PubMed  Google Scholar 

  16. Boesiger J, Tsai M, Maurer M, et al. Mast cells can secrete vascular permeability factor/vascular endothelial cell growth factor and exhibit enhanced release after immunoglobulin E-dependent upregulation of fc epsilon receptor I expression. J Exp Med. 1998;188(6):1135–45.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Hershko AY, Suzuki R, Charles N, et al. Mast cell interleukin-2 production contributes to suppression of chronic allergic dermatitis. Immunity. 2011;35(4):562–71.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. da Silva EZ, Jamur MC, Oliver C. Mast cell function: a new vision of an old cell. J Histochem Cytochem. 2014;62(10):698–738.

    Article  PubMed  PubMed Central  Google Scholar 

  19. Guldur ME, Kocarslan S, Ozardali HI, Ciftci H, Dincoglu D, Gumus K. The relationship of mast cells and angiogenesis with prognosis in renal cell carcinoma. JPMA. 2014;64(3):300–3.

    Google Scholar 

  20. Tuna B, Yorukoglu K, Unlu M, Mungan MU, Kirkali Z. Association of mast cells with microvessel density in renal cell carcinomas. Eur Urol. 2006;50(3):530–4.

    Article  PubMed  Google Scholar 

  21. Zisman A, Pantuck AJ, Wieder J, et al. Risk group assessment and clinical outcome algorithm to predict the natural history of patients with surgically resected renal cell carcinoma. J Clin Oncol. 2002;20(23):4559–66.

    Article  PubMed  Google Scholar 

  22. Fu H, Liu Y, Xu L, et al. Galectin-9 predicts postoperative recurrence and survival of patients with clear-cell renal cell carcinoma. Tumour Biol. 2015;36(8):5791–9.

    Article  CAS  PubMed  Google Scholar 

  23. Newman AM, Liu CL, Green MR, et al. Robust enumeration of cell subsets from tissue expression profiles. Nat Methods. 2015;12(5):453–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Blair RJ, Meng H, Marchese MJ, et al. Human mast cells stimulate vascular tube formation. Tryptase is a novel, potent angiogenic factor. J Clin Investig. 1997;99(11):2691–700.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Saleem SJ, Martin RK, Morales JK, et al. Cutting edge: mast cells critically augment myeloid-derived suppressor cell activity. J Immunol. 2012;189(2):511–5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Ribatti D. Mast cells and macrophages exert beneficial and detrimental effects on tumor progression and angiogenesis. Immunol Lett. 2013;152(2):83–8.

    Article  CAS  PubMed  Google Scholar 

  27. Ozdemir O. Flow cytometric mast cell-mediated cytotoxicity assay: a three-color flow cytometric approach using monoclonal antibody staining with annexin V/propidium iodide co-labeling to assess human mast cell-mediated cytotoxicity by fluorosphere-adjusted counts. J Immunol Methods. 2011;365(1–2):166–73.

    Article  PubMed  Google Scholar 

  28. Huang B, Lei Z, Zhang GM, et al. SCF-mediated mast cell infiltration and activation exacerbate the inflammation and immunosuppression in tumor microenvironment. Blood. 2008;112(4):1269–79.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Ribatti D, Crivellato E. Mast cells, angiogenesis and cancer. Adv Exp Med Biol. 2011;716:270–88.

    Article  CAS  PubMed  Google Scholar 

  30. Buonerba C, Di Lorenzo G, Sonpavde G. Combination therapy for metastatic renal cell carcinoma. Ann Transl Med. 2016;4(5):100.

    Article  Google Scholar 

  31. Ravaud A, Motzer RJ, Pandha HS, et al. Adjuvant sunitinib in high-risk renal-cell carcinoma after nephrectomy. N Engl J Med. Oct 9 2016.

  32. Fleischmann A, Schlomm T, Kollermann J, et al. Immunological microenvironment in prostate cancer: high mast cell densities are associated with favorable tumor characteristics and good prognosis. Prostate. 2009;69(9):976-81.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgement

This study was funded by grants from National Key Projects for Infectious Diseases of China (2012ZX10002012-007, 2016ZX10002018-008), National Natural Science Foundation of China (31270863, 81402082, 81402085, 81471621, 81472227 and 81671628), Program for New Century Excellent Talents in University (NCET-13-0146), Shanghai Municipal Natural Science Foundation (16ZR1406500), Shanghai Municipal Commission of Health and Family Planning Program (20144Y0223) and Innovation Project of Shanghai Jiao Tong University School of Medicine (16XJ21001, 16XJ21003). All study sponsors have no roles in the study design, in the collection, analysis, and interpretation of data.

Authors’ Contributions

H Fu, Y. Zhu, and Y. Wang and for acquisition of data, analysis, and interpretation of data, statistical analysis, and drafting of the manuscript. Z. Liu, J. Zhang, Z. Wang, H. Xie, and B. Dai for technical and material support. J. Xu and D. Ye for study concept and design, analysis and interpretation of data, drafting of the manuscript, obtained funding, and study supervision. All authors read and approved the final manuscript.

Conflict of interest

The authors declare no conflict of interest.

Author information

Author notes

    Authors and Affiliations

    1. Department of Urology, Fudan University Shanghai Cancer Center, Shanghai, China

      Hangcheng Fu MD, Yu Zhu MD, Zheng Liu MD, Junyu Zhang MD, Huyang Xie MD, Bo Dai MD & Dingwei Ye MD

    2. Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China

      Hangcheng Fu MD, Yu Zhu MD, Zheng Liu MD, Junyu Zhang MD, Huyang Xie MD, Bo Dai MD & Dingwei Ye MD

    3. Department of Urology, Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China

      Yiwei Wang MD

    4. Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fudan University, Shanghai, China

      Zewei Wang MD & Jiejie Xu MD, PhD

    Authors
    1. Hangcheng Fu MD
      View author publications

      You can also search for this author in PubMed Google Scholar

    2. Yu Zhu MD
      View author publications

      You can also search for this author in PubMed Google Scholar

    3. Yiwei Wang MD
      View author publications

      You can also search for this author in PubMed Google Scholar

    4. Zheng Liu MD
      View author publications

      You can also search for this author in PubMed Google Scholar

    5. Junyu Zhang MD
      View author publications

      You can also search for this author in PubMed Google Scholar

    6. Zewei Wang MD
      View author publications

      You can also search for this author in PubMed Google Scholar

    7. Huyang Xie MD
      View author publications

      You can also search for this author in PubMed Google Scholar

    8. Bo Dai MD
      View author publications

      You can also search for this author in PubMed Google Scholar

    9. Jiejie Xu MD, PhD
      View author publications

      You can also search for this author in PubMed Google Scholar

    10. Dingwei Ye MD
      View author publications

      You can also search for this author in PubMed Google Scholar

    Corresponding authors

    Correspondence to Jiejie Xu MD, PhD or Dingwei Ye MD.

    Additional information

    Hangcheng Fu, Yu Zhu and Yiwei Wang have contributed equally to this work.

    Electronic supplementary material

    Below is the link to the electronic supplementary material.

    Supplementary material 1 (DOCX 17 kb)

    Supplementary material 2 (DOCX 17 kb)

    Supplementary material 3 (DOCX 16 kb)

    10434_2016_5702_MOESM4_ESM.tif

    Figure S1 Consort Diagram outlining patient selection criteria and exclusion criteria. In the figure, n1 and n2 represent the training cohort and validation cohort respectively (TIFF 7448 kb)

    10434_2016_5702_MOESM5_ESM.tif

    Figure S2 Tryptase expression in clear-cell renal cell carcinoma (ccRCC) tissues. (A) Peritumoral mast cells (MCs) infiltration with 200 × magnification. (B) Peritumoral mast cells (MCs) infiltration with 400 × magnification. (C) Intratumoral mast cells (MCs) sparse infiltration with 200 × magnification. (D) Intratumoral mast cells (MCs) sparse infiltration with 400 × magnification. (E) Intratumoral mast cells (MCs) abundant infiltration with 200 × magnification. (F) Intratumoral mast cells (MCs) abundant infiltration with 400 × magnification. (TIFF 16508 kb)

    10434_2016_5702_MOESM6_ESM.tif

    Figure S3 Raw data of mast cell density and mast cell distribution density in peritumoral tissue, intratumoral tissue of training set and validation set. (A). Mast cells density against survival in months of peritumoral tissue of training set. (B) Mast cells distribution density of peritumoral tissue of training set. (C) Mast cells density against survival in months of intratumoral tissue of training set. (D) Mast cells distribution density of intratumoral tissue of training set. (E) Mast cells density against survival in months of intratumoral tissue of validation set. (F) Mast cells distribution density of intratumoral tissue of validation set. (TIFF 19622 kb)

    10434_2016_5702_MOESM7_ESM.tif

    Figure S4 Nomogram and calibration plot for prediction of clinical outcomes in patients with clear-cell renal cell carcinoma (ccRCC). (A) Cancer-specific survival. (B) Relapse-free survival. (TIFF 11035 kb)

    10434_2016_5702_MOESM8_ESM.tif

    Figure S5 Kaplan–Meier analysis of overall survival of patients with clear-cell renal cell carcinoma (ccRCC) based on mast cells infiltration with TCGA cohort according to LM22 genotype profile. P value was calculated by log-rank test. (TIFF 8352 kb)

    Rights and permissions

    Reprints and permissions

    About this article

    Check for updates. Verify currency and authenticity via CrossMark

    Cite this article

    Fu, H., Zhu, Y., Wang, Y. et al. Tumor Infiltrating Mast Cells (TIMs) Confers a Marked Survival Advantage in Nonmetastatic Clear-Cell Renal Cell Carcinoma. Ann Surg Oncol 24, 1435–1442 (2017). https://doi.org/10.1245/s10434-016-5702-5

    Download citation

    • Received:

    • Published:

    • Issue Date:

    • DOI: https://doi.org/10.1245/s10434-016-5702-5

    Keywords

    Search

    Navigation