Prognostic impact of tumor infiltrating lymphocytes on patients with metastatic urothelial carcinoma receiving platinum based chemotherapy

Hui-Shan Huang, Harvey Yu-Li Su, Pei-Hsu Li, Po-Hui Chiang, Cheng-Hua Huang, Chien-Hsu Chen, Meng-Che Hsieh, Hui-Shan Huang, Harvey Yu-Li Su, Pei-Hsu Li, Po-Hui Chiang, Cheng-Hua Huang, Chien-Hsu Chen, Meng-Che Hsieh

Abstract

The impact of tumor infiltrating lymphocytes (TILs) on survival was confirmed in various cancer types. Our study aims to investigate the prognostic role of TILs on survival in patients with metastatic urothelial carcinoma (mUC) receiving platinum based chemotherapy. Patients who were diagnosed to have pathologically proved mUC between 1997 and 2016 and received palliative chemotherapy with platinum based regimen were recruited into our study. Kaplan-Meier curves and Cox regression analysis were constructed for overall survival (OS). A total of 259 mUC patients were enrolled into our study with median age 63 years and median follow-up visit 13.5 months. Of these patients, 179 (69%) had intense TILs and 80 (31%) had non-intense TILs. The median OS were 15.7 vs. 6.7 months (P = < 0.001) for patients with intense TILs and non-intense TILs, respectively. Subgroup analysis showed that TILs was both prognostically significant no matter for urothelial carcinoma of bladder and upper tract urothelial carcinoma. Multivariate analysis showed that TILs were strongly prognostic factors related to OS. Our study suggested mUC patients with intense TILs were independently associated with survival. Based on our study, TILs is clinically useful for outcomes anticipation and risk stratification, as well as patients counseling.

Conflict of interest statement

The authors declare no competing interests.

Figures

Figure 1
Figure 1
Kaplan-Meier overall survival curve of 259 patients with mUC, stratified by TILs.
Figure 2
Figure 2
Kaplan-Meier overall survival curve of patients with UCB and UTUC, stratified by TILs.
Figure 3
Figure 3
Representative urothelial carcinoma specimens stained with haematoxylin and eosin (H&E 100X) demonstrating examples with (A) intense intratumoral tumor infiltrating lymphocytes (itTILs) (black arrows), (B) intense stromal tumor infiltrating lymphocytes (sTILs) (black arrows).

References

    1. Siegel R, Naishadham D, Jemal A. Cancer statistics, 2013. CA Cancer J Clin. 2013;63:11–30. doi: 10.3322/caac.21166.
    1. Witjes JA, et al. Updated 2016 EAU guidelines on muscle-invasive and Metastatic Bladder Cancer. Eur Urol. 2017;71:462–75. doi: 10.1016/j.eururo.2016.06.020.
    1. von der Maase H, et al. Gemcitabine and Cisplatin Versus Methotrexate, Vinblastine, Doxorubicin, and Cisplatin in Advanced or Metastatic Bladder Cancer Results of a Large, Randomized, Multinational, Multicenter, Phase III Study. J Clin Oncol. 2000;18:3068–77. doi: 10.1200/JCO.2000.18.17.3068.
    1. von der Maase H, et al. Long-term survival results of a randomized trial comparing gemcitabine plus cisplatin, with methotrexate, vinblastine, doxorubicin, plus cisplatin in patients with bladder cancer. J Clin Oncol. 2005;23:4602–8. doi: 10.1200/JCO.2005.07.757.
    1. De Santis M, et al. Randomized Phase II/III Trial Assessing Gemcitabine/Carboplatin and Methotrexate/Carboplatin/Vinblastine in Patients With Advanced Urothelial Cancer Who Are Unfit for Cisplatin-Based Chemotherapy: EORTC Study 30986. Journal of Clinical Oncology. 2012;30:191–9. doi: 10.1200/JCO.2011.37.3571.
    1. Galsky M, et al. Comparative effectiveness of cisplatin-based and carboplatin-based chemotherapy for treatment of advanced urothelial carcinoma. Ann Oncol. 2012;23:406–10. doi: 10.1093/annonc/mdr156.
    1. Hsieh M-C, et al. The Prognostic Impact of Histopathological Variants in Patients with Advanced Urothelial Carcinoma. Plos One. 2015;10:e0129268. doi: 10.1371/journal.pone.0129268.
    1. Ku JH, et al. Lymphovascular invasion as a prognostic factor in the upper urinary tract urothelial carcinoma: a systematic review and meta-analysis. Eur. J. Cancer. 2013;49:2665–80. doi: 10.1016/j.ejca.2013.04.016.
    1. Colin P, et al. Influence of positive surgical margin status after radical nephroureterectomy on upper urinary tract urothelial carcinoma survival. Ann. Surg. Oncol. 2012;19:3613–20. doi: 10.1245/s10434-012-2453-9.
    1. Bajorin DF, et al. Long-term survival in metastatic transitional-cell carcinoma and prognostic factors predicting outcome of therapy. J Clin Oncol. 1999;17:3173–81. doi: 10.1200/JCO.1999.17.10.3173.
    1. Taguchi S, et al. Prognostic factors for metastatic urothelial carcinoma undergoing cisplatin-based salvage chemotherapy. Jpn J Clin Oncol. 2013;43:923–8. doi: 10.1093/jjco/hyt096.
    1. Tanaka N, et al. Patient characteristics and outcomes in metastatic upper tract urothelial carcinoma after radical nephroureterectomy: the experience of Japanese multi-institutions. BJU Int. 2013;112:E28–34. doi: 10.1111/bju.12133.
    1. Solinas C, et al. The immune infiltrate in prostate, bladder and testicular tumors: An old friend for new challenges. Cancer Treatment Reviews. 2017;53:138–45. doi: 10.1016/j.ctrv.2016.12.004.
    1. de Visser KE, Eichten A, LM C. Paradoxical roles of the immune system during cancer development. Nat Rev Cancer. 2006;6:24–37. doi: 10.1038/nrc1782.
    1. Gooden MJM, et al. The prognostic influence of tumour-infiltrating lymphocytes in cancer: a systematic review with meta-analysis. Br J Cancer. 2011;105:93–103. doi: 10.1038/bjc.2011.189.
    1. Adams S, et al. Prognostic Value of Tumor-Infiltrating Lymphocytes in Triple-Negative Breast Cancers From Two Phase III Randomized Adjuvant Breast Cancer Trials: ECOG 2197 and ECOG 1199. Journal of Clinical Oncology. 2014;32:2959–66. doi: 10.1200/JCO.2013.55.0491.
    1. Goff SL, et al. Randomized, Prospective Evaluation Comparing Intensity of Lymphodepletion Before Adoptive Transfer of Tumor-Infiltrating Lymphocytes for Patients With Metastatic Melanoma. Journal of Clinical Oncology. 2016;34:2389–97. doi: 10.1200/JCO.2016.66.7220.
    1. Bremnes RM, et al. The Role of Tumor-Infiltrating Lymphocytes in Development, Progression, and Prognosis of Non–Small Cell Lung Cancer. Journal of Thoracic Oncology. 2016;11:789–800. doi: 10.1016/j.jtho.2016.01.015.
    1. Webb JR, et al. Tumor-Infiltrating Lymphocytes Expressing the Tissue Resident Memory Marker CD103 Are Associated with Increased Survival in High-Grade Serous Ovarian Cancer. Clinical Cancer Research. 2013;20:434–44. doi: 10.1158/1078-0432.CCR-13-1877.
    1. Gilbert DC, et al. Tumour-infiltrating lymphocyte scores effectively stratify outcomes over and above p16 post chemo-radiotherapy in anal cancer. British Journal of Cancer. 2016;114:134–7. doi: 10.1038/bjc.2015.448.
    1. Ward MJ, et al. Tumour-infiltrating lymphocytes predict for outcome in HPV-positive oropharyngeal cancer. British Journal of Cancer. 2013;110:489–500. doi: 10.1038/bjc.2013.639.
    1. Tomioka N, et al. The therapeutic candidate for immune checkpoint inhibitors elucidated by the status of tumor-infiltrating lymphocytes (TILs) and programmed death ligand 1 (PD-L1) expression in triple negative breast cancer (TNBC) Breast Cancer. 2017;25:34–42. doi: 10.1007/s12282-017-0781-0.
    1. Topalian SL, et al. Mechanism-driven biomarkers to guide immune checkpoint blockade in cancer therapy. Nature Reviews Cancer. 2016;16:275–87. doi: 10.1038/nrc.2016.36.
    1. Baras AlexanderS, et al. The ratio of CD8 to Treg tumor-infiltrating lymphocytes is associated with response to cisplatin-based neoadjuvant chemotherapy in patients with muscle invasive urothelial carcinoma of the bladder. OncoImmunology. 2016;5:e1134412. doi: 10.1080/2162402X.2015.1134412.
    1. Wang B, et al. CD103+ Tumor Infiltrating Lymphocytes Predict a Favorable Prognosis in Urothelial Cell Carcinoma of the Bladder. The Journal of Urology. 2015;194:556–62. doi: 10.1016/j.juro.2015.02.2941.
    1. Perez EdithA, et al. Association of Stromal Tumor-Infiltrating Lymphocytes With Recurrence-Free Survival in the N9831 Adjuvant Trial in Patients With Early-Stage HER2-Positive Breast Cancer. JAMA Oncol. 2016;2:56–64. doi: 10.1001/jamaoncol.2015.3239.
    1. Loi S, et al. Prognostic and Predictive Value of Tumor-Infiltrating Lymphocytes in a Phase III Randomized Adjuvant Breast Cancer Trial in Node-Positive Breast Cancer Comparing the Addition of Docetaxel to Doxorubicin With Doxorubicin-Based Chemotherapy: BIG 02-98. Journal of Clinical Oncology. 2013;31:860–7. doi: 10.1200/JCO.2011.41.0902.
    1. Loi SSN, et al. Prognostic and predictive value of tumor-infiltrating lymphocytes in a phase III randomized adjuvant breast cancer trial in node-positive breast cancer comparing the addition of docetaxel to doxorubicin with doxorubicin-based chemotherapy: BIG 02–98. J Clin Oncol. 2013;31:860–7. doi: 10.1200/JCO.2011.41.0902.
    1. Fridman WH, Pages F, Sautes-Fridman C, Galon J. The immune contexture in human tumours: impact on clinical outcome. Nat Rev Cancer. 2012;12:298–306. doi: 10.1038/nrc3245.
    1. Galon J, Fridman WH, F P. The adaptive immunologic microenvironment in colorectal cancer: a novel perspective. Cancer Res. 2007;67:1883–6. doi: 10.1158/0008-5472.CAN-06-4806.
    1. Badoual C, et al. Better understanding tumor-host interaction in head and neck cancer to improve the design and development of immunotherapeutic strategies. Head Neck. 2010;32:946–58.
    1. Shuzhen Liu WilliamD, et al. Prognostic significance of FOXP3+ tumor-infiltrating lymphocytes in breast cancer depends on estrogen receptor and human epidermal growth factor receptor-2 expression status and concurrent cytotoxic T-cell infiltration. Breast Cancer Research. 2014;16:432–43. doi: 10.1186/s13058-014-0432-8.
    1. Djenidi F, et al. CD8+CD103+ Tumor–Infiltrating Lymphocytes Are Tumor-Specific Tissue-Resident Memory T Cells and a Prognostic Factor for Survival in Lung Cancer Patients. The Journal of Immunology. 2015;194:3475–86. doi: 10.4049/jimmunol.1402711.
    1. Zhang B, et al. Prognostic significance of PD-L1 expression on tumor cells and tumor-infiltrating mononuclear cells in upper tract urothelial carcinoma. Medical Oncology. 2017;34:94–9. doi: 10.1007/s12032-017-0941-2.
    1. Sjödahl G, et al. Infiltration of CD3+ and CD68+ cells in bladder cancer is subtype specific and affects the outcome of patients with muscle-invasive tumors11Grant support: The Swedish Cancer Society, the Swedish research council, the Nilsson Cancer foundation, the BioCARE Strategic Cancer Research program, the Lund Medical Faculty, and FoU Landstinget Kronoberg and Södra Regionvårdnämnden. Urologic Oncology: Seminars and Original Investigations. 2014;32:791–7. doi: 10.1016/j.urolonc.2014.02.007.
    1. Bellmunt J, et al. Association of PD-L1 expression on tumor-infiltrating mononuclear cells and overall survival in patients with urothelial carcinoma. Annals of Oncology. 2015;26:812–7. doi: 10.1093/annonc/mdv009.
    1. Loi S, et al. RAS/MAPK Activation Is Associated with Reduced Tumor-Infiltrating Lymphocytes in Triple-Negative Breast Cancer: Therapeutic Cooperation Between MEK and PD-1/PD-L1 Immune Checkpoint Inhibitors. Clinical Cancer Research. 2015;22:1499–509. doi: 10.1158/1078-0432.CCR-15-1125.
    1. Hamid O, et al. Safety and tumor responses with lambrolizumab (anti-PD-1) in melanoma. N Engl J Med. 2013;369:134–44. doi: 10.1056/NEJMoa1305133.
    1. Tumeh PC, et al. PD-1 blockade induces responses by inhibiting adaptive immune resistance. Nature. 2014;515:568–71. doi: 10.1038/nature13954.
    1. Salgado R, et al. The evaluation of tumor-infiltrating lymphocytes (TILs) in breast cancer: recommendations by an International TILs Working Group 2014. Annals of Oncology. 2015;26:259–71. doi: 10.1093/annonc/mdu450.
    1. Rouanne Mathieu, et al. Association of stromal lymphocyte infiltration with tumor invasion depth and high-grade T1 bladder cancer. J Clin Oncol. 2018;36:488–488. doi: 10.1200/JCO.2018.36.6_suppl.488.

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