The Role of PD-L1 Expression and Intratumoral Lymphocytes in Response to Perioperative Chemotherapy for Urothelial Carcinoma

F Erlmeier, A K Seitz, G Hatzichristodoulou, L Stecher, M Retz, J E Gschwend, W Weichert, H R Kübler, T Horn, F Erlmeier, A K Seitz, G Hatzichristodoulou, L Stecher, M Retz, J E Gschwend, W Weichert, H R Kübler, T Horn

Abstract

Introduction: Immunological pathways are relevant for the effectiveness of conventional cytotoxic chemotherapy. Recently, checkpoint inhibition of the PD-1/PD-L1 axis has been shown to be therapeutically relevant in urothelial carcinoma. Objective: To monitor PD-L1 expression on tumor cells and intratumoral infiltration with CD8 positive lymphocytes during perioperative chemotherapy for urothelial cancer and to evaluate their use as potential predictive markers for chemotherapy. Patients and Methods: Sixty-four patients with muscle-invasive urothelial cancer were included in the analysis. Twenty-two patients received preoperative chemotherapy and 42 were treated in an adjuvant setting for locally advanced disease or lymph node metastases. PD-L1 status and the density of infiltration with CD8-positive cells were assessed by immunohistochemistry and analysed for their association with survival (adjuvant group) and response to chemotherapy (preoperative group). For PD-L1 positivity we used a cutoff of 10% positive tumor cells. Results: In the adjuvant group, 11 of 42 patients (26.2%) had PD-L1 positive tumor cells. Twenty-six of 42 (61.9%) patients were highly infiltrated with CD8 + lymphocytes. There was no significant evidence of an association with overall survival for PD-L1 status nor for CD8 infiltration density (p = 0.63 and 0.71). In the preoperative group, eight of the 22 (36.4%) patients were PD-L1 positive and 13 (59%) were highly infiltrated with CD8 + lymphocytes before chemotherapy. There was no evidence of associations with response or survival. Eight patients showed a pathological response to preoperative treatment. These had a significantly longer overall survival than non-responders (p = 0.01). In the preoperative group the pre-treatment expression of the immunologic markers could be compared to the post-treatment status. Only one patient showed a changed PD-L1 status and three patients a changed CD8 status. Conclusions: The tumoral expression of PD-L1 in urothelial carcinoma does not seem to be largely influenced by chemotherapy. Our data do not provide evidence that tumoral expression of PD-L1 and CD8 are useful as prognostic or predictive markers. Small sample size is the major limitation of our study.

Keywords: PD-L1; bladder cancer; perioperative chemotherapy.

Figures

Fig.1
Fig.1
Exemplary stains for PD-L1 and CD8. From top to bottom: PD-L1 positive tumor, 20x; positive control (human placenta) for PD-L1, 20x; CD8 infiltration, 20x.
Fig.2
Fig.2
Patients with a response to neoadjuvant treatment had a significantly prolonged overall survival in comparison to non-reponders, p = 0.01.
Fig.3
Fig.3
Kaplan-Meier estimates of survival according to PD-L1 tumor status in the adjuvant group. X axis: Overall survival in months. p = 0.63.
Fig.4
Fig.4
Kaplan-Meier estimates of survival according to PD-L1 tumor status in the neoadjuvant group. X axis: Overall survival in months. p = 0.97.
Fig.5
Fig.5
Kaplan-Meier estimates of survival according to intratumoral CD8 infiltration density in the adjuvant group. p = 0.71.
Fig.6
Fig.6
Kaplan-Meier estimates of survival according to intratumoral CD8 infiltration density in the neoadjuvant group. p = 0.61.

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