Seminars Article
Myeloid-derived suppressors cells (MDSC) correlate with clinicopathologic factors and pathologic complete response (pCR) in patients with urothelial carcinoma (UC) undergoing cystectomy

https://doi.org/10.1016/j.urolonc.2018.02.018Get rights and content

Highlights

  • MDSCs are immunosuppressive cells with potential predictive and prognostic role in UC.

  • MDSC subsets can predict pCR in UC patients undergoing cystectomy.

  • Circulating MDSCs are associated with NLR and squamous features.

  • Additional MDSC analyses in localized and metastatic UC are ongoing.

Abstract

Background

Myeloid derived suppressor cells (MDSC) are heterogeneous immunosuppressive cells with potential predictive and prognostic roles in cancer. The association between MDSC, clinicopathologic factors, and pathologic response in patients with bladder urothelial carcinoma (UC) was explored.

Methods

Peripheral blood or tissue were collected from patients with UC undergoing definitive surgery. MDSCs levels were measured in peripheral blood mononuclear cells and fresh tumor tissue. MDSCs were identified by flow cytometry and defined as total MDSC (T-MDSC) CD33+/HLADR−. From this population, 3 subsets were identified: polymorphonuclear-MDSC (PMN-MDSC) defined as CD33+/HLADR−/CD15+/CD14-, monocytic-MDSC (M-MDSC) defined as CD33+/HLADR-/CD15-/CD14+, and immature-MDSC (I-MDSC) defined as CD33+/HLADR−/CD15−/CD14−. MDSC populations were presented as % of live nucleated blood cells. Spearman correlations (r) and Wilcoxon rank sum test were used to assess correlations between MDSC populations, clinicopathologic factors, and pathologic complete response (pCR).

Results

85 patients scheduled to undergo cystectomy from February 2015 through Dec 2016 were included. All patients had blood drawn for analysis and 23 patients had residual tumor tissue collected for analysis at the time of surgery. Of these 85, 74 (87%) were men with a median age at diagnosis of 68 (range: 44–87). Pure UC was the most common histology (75%); 28 (35%) patients had prior treatment with intravesical therapy and 36 (42%) were treated with neoadjuvant chemotherapy, primarily gemcitabine plus cisplatin (n = 24). On surgical pathology, 18 (21%) of the patients had pCR, 11 (13%) had positive lymph nodes, and 20 patients (24%) had lymphovascular invasion. Statistically significant associations were found between circulating MDSC levels and pCR rates (P<0.01), absolute neutrophil-lymphocyte ratio (P = 0.008), and histology (P = 0.01). Tumor % M-MDSCs were negatively associated with lymphovascular invasion (P = 0.04). There were no significant correlations between peripheral blood mononuclear cells and tumor MDSC subtypes.

Conclusions

Blood and tissue MDSC levels correlate with several clinicopathologic factors and may predict for pCR. Future studies are needed to highlight the role of MDSC in predicting long-term outcomes and to determine the clinical implications of these findings.

Introduction

Bladder cancer is the most common cancer of the urinary tract with urothelial carcinoma (UC) as its most common histologic type [1]. Approximately 20% to 40% of patients have muscle-invasive urothelial carcinoma (MIUC) either at initial diagnosis or following progression from a previously non–muscle-invasive tumor state [2]. Radical cystectomy and bilateral pelvic lymph node (LN) dissection remains the standard treatment for most patients with nonmetastatic MIUC, and neoadjuvant cisplatin-based chemotherapy improves long-term survival compared to patients undergoing surgery alone [3].

The clinical and pathological features at the time of cystectomy can be prognostic for disease recurrence and long-term outcomes for patients with MIUC. In particular, the presence of lymph node (LN) involvement, higher tumor stage, and lymphovascular invasion (LVI) are poor prognostic factors [4], [5]. Conversely, a complete pathological response (pCR) following cystectomy predicts for improved progression-free survival and overall survival (OS) [6], [7], [8], [9]. To date, limited biomarkers exist to predict surgical pathological outcomes at the time of cystectomy [10]. Such data could be useful in a variety of settings including potentially favoring a bladder-sparing definitive therapy or guide future surveillance approaches instead of radical cystectomy for patients who have a pCR to neoadjuvant chemotherapy [11], [12], [13], [14], [15].

Myeloid derived suppressor cells (MDSCs) are a phenotypically diverse population of bone marrow-derived cells that play an important role in tumor progression based on their immunosuppressive and proangiogenic properties [16]. Circulating MDSCs have been shown to correlate with stage, tumor burden, treatment response, and clinical outcomes in a variety of cancers [17], [18], [19]. Circulating MDSC subsets have been previously shown to be highly proliferating and activate a host of proinflammatory cytokines in patients with bladder cancer [20]. In this study, the correlation between blood and tissue MDSCs, clinicopathologic features, and neoadjuvant treatment outcomes in patients with MIUC undergoing radical cystectomy was investigated.

Section snippets

Patients

Patients with UC of the bladder who were scheduled to undergo cystectomy were all consented on an IRB approved protocol (Cleveland Clinic IRB 14–1222, approval date February 12, 2015) for blood and tissue collection prior to surgery. All surgical patients were considered for inclusion regardless of prior intravesical therapy or neoadjuvant chemotherapy. Patients with metastatic disease at the time of surgery were excluded from the analysis, with the exception of patients with only regional

Patient characteristics

Overall, 85 patients who underwent cystectomy for UC between February 25, 2015 and December 22, 2016 were included in the analysis. All patients had blood drawn for analysis and 23 patients had available residual tumor tissue collected for analysis at the time of surgery. Most of the patients (91%, n = 77) had blood drawn within 3 days of surgery; only 8 patients had blood drawn between 4 and 15 days prior to surgery.

Of the 85 patients, 74 (87%) were men with median age at diagnosis of 68

Discussion

MDSCs are immunosuppressive cells that have predictive and prognostic roles in patients with solid tumors [17], [19]. Limited data is published regarding the role of circulating and tissue MDSCs in patients with UC. The fundamental findings of this study are that specific subsets of MDSCs correlate with clinicopathologic features at the time of cystectomy in patients with MIUC undergoing cystectomy. Specifically, this study highlights that there are significant associations between circulating

Conclusions

In conclusion, blood and tissue MDSC levels correlate with several clinicopathologic factors and are associated with pCR. Future studies are needed to highlight the role and function of MDSC in predicting long-term outcomes and to determine the clinical implications of these findings.

References (45)

  • J.E. Rosenberg et al.

    Atezolizumab in patients with locally advanced and metastatic urothelial carcinoma who have progressed following treatment with platinum-based chemotherapy: a single-arm, multicentre, phase 2 trial

    Lancet

    (2016)
  • A.V. Balar et al.

    Atezolizumab as first-line treatment in cisplatin-ineligible patients with locally advanced and metastatic urothelial carcinoma: a single-arm, multicentre, phase 2 trial

    Lancet

    (2017)
  • P. Sharma et al.

    Nivolumab in metastatic urothelial carcinoma after platinum therapy (CheckMate 275): a multicentre, single-arm, phase 2 trial

    Lancet Oncol

    (2017)
  • R.L. Siegel et al.

    Cancer statistics, 2017

    CA Cancer J Clin

    (2017)
  • Neoadjuvant chemotherapy in invasive bladder cancer: update of a systematic review and meta-analysis of individual patient data advanced bladder cancer (ABC) meta-analysis collaboration

    Eur Urol.

    (2005)
  • V. Margulis et al.

    Predicting survival after radical cystectomy for bladder cancer

    BJU Int

    (2008)
  • E.R. Plimack et al.

    Accelerated methotrexate, vinblastine, doxorubicin, and cisplatin is safe, effective, and efficient neoadjuvant treatment for muscle-invasive bladder cancer: results of a multicenter phase II study with molecular correlates of response and toxicity

    J Clin Oncol

    (2014)
  • H.B. Grossman et al.

    Neoadjuvant chemotherapy plus cystectomy compared with cystectomy alone for locally advanced bladder cancer

    N Engl J Med

    (2003)
  • T.K. Choueiri et al.

    Neoadjuvant dose-dense methotrexate, vinblastine, doxorubicin, and cisplatin with pegfilgrastim support in muscle-invasive urothelial cancer: pathologic, radiologic, and biomarker correlates

    J Clin Oncol

    (2014)
  • G.S. Kulkarni et al.

    Propensity score analysis of radical cystectomy versus bladder-sparing trimodal therapy in the setting of a multidisciplinary bladder cancer clinic

    J Clin Oncol

    (2017)
  • C.N. Sternberg et al.

    Can patient selection for bladder preservation be based on response to chemotherapy?

    Cancer

    (2003)
  • H.W. Herr

    Transurethral resection of muscle-invasive bladder cancer: 10-year outcome

    J Clin Oncol.

    (2001)
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