Abstract
Platinum-based chemotherapy is the standard of care in metastatic bladder cancer. With the approval of various checkpoint inhibitors, immunotherapy has revolutionized the traditional treatment modalities. The aim of the study was to evaluate whether PD-L1 expression on tumor cells (TCs) and tumor-infiltrating immune cells (ICs) can be used as biomarker to predict recurrence-free survival (RFS), overall survival (OS) and disease-specific survival (DSS) in bladder cancer patients after radical cystectomy (RC) developing disease recurrence followed by first-line chemotherapy. PD-L1 was measured on formalin-fixed, paraffin-embedded tissue sections of RC specimens in all patients (n=61) and in 27 matched metastatic biopsy samples by immunohistochemistry. PD-L1 expression on TCs was defined by the percentage of PD-L1 positive tumor cells (< 1%= IC0, ≥1% but <5%=IC1, ≥5 %=IC2/3), and was considered negative or positive for ICs. On 27 paired samples, IC1/2/3 score on TCs was homogeneous distributed with 59.3% in primary tumors and metastases, but with a high discordance rate of 44.4% of PD-L1 positivity on ICs. High PD-L1 expression (IC2/3) on TCs was more frequently seen in histologic subtypes of urothelial cancer compared to pure urothelial cancers (46.2% vs. 20.8%; p=0.002). PD-L1 expression on TCs in primary tumors (IC2/3 vs. IC0, median: 3.2 vs. 13.8 months, p=0.019) and metastatic sites (IC2/3 vs. IC0, median: 6.1 vs. 21.8 months, p=0.014) was associated with poor chemo-response, represented by significant shortened DSS. These results suggest that PD-L1 may be a potential target being involved in chemo-resistance mechanisms and poses potential for therapy stratification in the future.
Highlights
Bladder cancer is a highly immunogenic malignancy, including T cell-inflamed and non-T cellinflamed tumors [1]
The aim of the study was to evaluate whether PDL1 expression on tumor cells (TCs) and tumor-infiltrating immune cells (ICs) can be used as biomarker to predict recurrence-free survival (RFS), overall survival (OS) and disease-specific survival (DSS) in bladder cancer patients after radical cystectomy (RC) developing disease recurrence followed by first-line chemotherapy
programed death –ligand 1 (PD-L1) expression was evaluated on TC as well as on tumor-infiltrating lymphocyte (TIL) of primary tumors (n=61) and in 27 available biopsies from metastatic sites
Summary
Bladder cancer is a highly immunogenic malignancy, including T cell-inflamed and non-T cellinflamed tumors [1]. Immune gene expression profiling identified three molecular pathways (B-catenin overexpression, FGF3 mutations and PPAR-g activation) linked to a non-T cell-inflamed tumor microenvironment, being responsible for intrinsic resistance to immunotherapies [7], Supplementary Figure 1. Low T cell receptor (TCR) clonality was noticed in pretreatment blood, whereas TIL clones expanded more rapid and robust during immunotherapy These findings underline the dynamic changes and complexity of the antitumor immune response during treatment with checkpoint inhibitors [13]. Claudin-low tumors, are resistant to cisplatin-based neoadjuvant chemotherapy [14] and represent a molecular subtype of bladder cancer with the highest expression of immune gene signatures, with an up-regulation of chemokines and cytokines from low PPAR-g activity, allowing continuous NFKB activity and consecutive pro-inflammatory milieu, being primed for immunotherapeutic response [15], Supplementary Figure 1. PD-L1 as a possible novel biomarker in predicting oncologic outcome in MIBC after radical cystectomy (RC) and therapeutic response to chemotherapy or checkpoint inhibitors remains a debated issue, with conflicting evidence [12, 16,17] and discordance between PD-L1 expression in primary tumors and metastatic sites [18]
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