Elsevier

European Urology

Volume 55, Issue 6, June 2009, Pages 1386-1396
European Urology

Bladder Cancer
Bladder Tumor Infiltrating Mature Dendritic Cells and Macrophages as Predictors of Response to Bacillus Calmette-Guérin Immunotherapy

https://doi.org/10.1016/j.eururo.2009.01.040Get rights and content

Abstract

Background

The clinical significance of tumor-infiltrating dendritic cells (TIDCs) and tumor-associated macrophages (TAMs) as markers of immune response has been reported for many cancers.

Objective

To measure tumor infiltration by CD83+ dendritic cells (DCs) and CD68+ macrophages in non–muscle-invasive urothelial cancer (NMIUC) prior to bacillus Calmette-Guérin (BCG) immunotherapy and to evaluate their significance in the response to immunotherapy.

Design, setting, and participants

Patients with NMIUC at high risk of recurrence and progression were recruited for a study on markers of the response to BCG.

Intervention

Patients were treated by transurethral resection followed by maintenance BCG.

Measurements

Immunohistochemical staining with anti-CD83 and anti-CD68 monoclonal antibodies on 53 and 46 NMIUC tumors, respectively, prior to BCG treatment. A scoring index was calculated based on the average density of positive cells within the papillary axis, the stroma, lymphoid aggregates, and infiltration into tumors.

Results and limitations

CD83+ TIDCs were observed mostly within lymphoid aggregates. Multivariate Cox regression analysis showed that maintenance BCG (more than one maintenance cycle) was highly effective in patients with a low level of CD83+ TIDCs at time of resection (hazard ratio [HR]: 0.035; p = 0.002) but showed reduced efficacy in patients with a high level of CD83+ TIDCs (HR: 0.87; p = 0.810). A high level of infiltration by CD83+ TIDCs slightly decreased the risk of recurrence in patients treated with one or no maintenance BCG cycle (HR: 0.4; p = 0.117). In the same population, a strong infiltration of CD68+ TAMs was associated with an increased risk of recurrence (HR: 3.8; p = 0.013).

Conclusions

These results suggest that patients with a high level of infiltration by CD83+ TIDCs or CD68+ TAMs do not respond as well to BCG immunotherapy. If confirmed in larger cohorts, the pretreatment level of infiltration by these cells may be useful to influence the choice of treatment strategy.

Introduction

Non–muscle-invasive bladder cancer (stages pTa, pT1, pTis) treated by transurethral surgery will recur in 60–70% of cases and will progress over time to muscle-invasive cancer in 15–25% of patients [1]. The assessment of the risk of recurrence and progression of tumors is an important step guiding the choice of the adjuvant treatment given to these patients [2], [3].

Intravesical instillations of bacillus Calmette-Guérin (BCG) is the most effective treatment to prevent recurrence and progression of high-risk non–muscle-invasive urothelial carcinoma (NMIUC) and to treat carcinoma in situ (Tis) [4]. Maintenance therapy, consisting of seven cycles of three weekly instillations at 3–6 mo intervals following an induction course of six weekly instillations, is suggested; however, full compliance is infrequent due to side effects [4], [5]. Approximately 30–40% of patients fail to respond to BCG immunotherapy [6]. These patients would fare better if they were oriented early to alternative therapies. Although some baseline characteristics have been shown to be independent predictors of progression [7], additional reliable markers of the response to BCG are still needed. Immunologic markers appear to be the most promising [8].

BCG provokes an inflammation involving the contribution of various immune cells including cells associated with the innate immune response. A marked increase in the number of macrophages and lymphocytes has been reported in patients’ voided urine after intravesical BCG therapy [9]. Dendritic cells (DCs) have also been suggested to play an important role in the response to mycobacteria [10]. Tumor infiltration by such immune cells has shown some association with prognosis in various cancers [11], [12], [13], [14], [15], [16], [17]. Because of their implication in defense against mycobacteria, we hypothesized that the level of bladder tumor infiltration by tumor-associated macrophages (TAMs) and tumor-infiltrating DCs (TIDCs) prior to BCG treatment might have an impact on the response.

In recent years, we prospectively recruited a cohort of patients treated with maintenance BCG for high-risk NMIUC. Initial characterization of the cohort led us to conclude that maintenance BCG effectively reduced recurrence of high-risk NMIUC but that at least two cycles of treatment beyond the induction course were necessary to demonstrate an effect [18]. In the present study, we used that cohort to evaluate the impact of the preexisting level of tumor infiltration by macrophages and DCs on the outcome of BCG immunotherapy.

Section snippets

Cohort of patients

The cohort of patients with NMIUC at high risk of recurrence and progression was recruited for a study of markers of response to BCG immunotherapy, with approval from local institutional review boards [18]. All patients signed an informed consent form. High risk was defined as the presence of at least one of the following criteria: previous recurrences within 6 mo, pT1 stage, more than three tumors, grade 3 out of 3, diffuse Tis, ≥3 cm in tumor diameter. At least 3 wk following transurethral

Pattern of tumor infiltration

Mature CD83+ DCs [20] were observed in the papillary axis of tumors, in the underlying stroma, rarely within tumors, and most frequently within lymphoid aggregates (Fig. 1a–d). A moderate or strong DC infiltration was observed in 28 of 53 tumors (54%) (Table 1). CD68+ TAMs were observed throughout tumor sections (Fig. 1e–h), namely within tumors, in the papillary axis, and in lymphoid aggregates, but mostly in the stroma, with the highest density at the tumor margin (Fig. 1h). A moderate or

Discussion

It has been suggested that both DCs and macrophages play an important role in the immune response to mycobacterial infection [10]. In this study, we investigated the prognostic potential of CD83+ TIDC and CD68+ TAMs in NMIUC prior to BCG treatment. TIDCs have been generally associated with a favorable prognosis in many human malignancies [11], [13]. We, however, observed a significant interaction between the level of TIDCs and the number of maintenance cycles of BCG, with different prognosis of

Conclusions

We observed a correlation between infiltration by CD83+ DCs and CD68+ macrophages in NMIUCs at time of TUR and the response to BCG. Patients with weak levels of tumor infiltration by either one of these two types of immune cells generally fared better in response to BCG maintenance immunotherapy. BCG was especially effective for patients with low levels of TIDCs. If confirmed in a larger cohort, these observations open the possibility of providing much needed new markers of the response to BCG

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