High Pretreatment Serum PD-L1 Levels Are Associated with Muscle Invasion and Shorter Survival in Upper Tract Urothelial Carcinoma

Abstract

Programmed death ligand-1 (PD-L1) is an immune checkpoint molecule and a widely used therapeutic target in urothelial cancer. Its circulating, soluble levels (sPD-L1) were recently suggested to be associated with the presence and prognosis of various malignancies but have not yet been investigated in upper tract urothelial carcinoma (UTUC). In this study, we assessed sPD-L1 levels in 97 prospectively collected serum samples from 61 UTUC patients who underwent radical nephroureterectomy (RNU), chemotherapy (CTX), or immune checkpoint inhibitor (ICI) therapy. In addition to pretreatment samples, postoperative and on-treatment sPD-L1 levels were determined in some patients by using ELISA. In the RNU group, elevated preoperative sPD-L1 was associated with a higher tumor grade (p = 0.019), stage (p < 0.001) and the presence of metastasis (p = 0.002). High sPD-L1 levels were significantly associated with worse survival in both the RNU and CTX cohorts. sPD-L1 levels were significantly elevated in postoperative samples (p = 0.011), while they remained unchanged during CTX. Interestingly, ICI treatment caused a strong, 25-fold increase in sPD-L1 (p < 0.001). Our results suggest that elevated preoperative sPD-L1 level is a predictor of higher pathological tumor stage and worse survival in UTUC, which therefore may help to optimize therapeutic decision-making. The observed characteristic sPD-L1 flare during immune checkpoint inhibitor therapy may have clinical significance.

Soluble immune checkpoints: implications for cancer prognosis and response to immune checkpoint therapy and conventional therapies

“…Similarly, patients with upper tract urothelial carcinoma with elevated sPD-L1 levels prior to therapy had a shorter duration of OS (median: ~ 10 months vs not reached at ~ 70 months, p = 0.006) following treatment with chemotherapy compared to patients with lower baseline levels (Fig. 4D) [89]. In small cell lung cancer patients receiving chemotherapy consisting of cisplatin-etoposide, elevated levels of sPD-L1 prior to therapy correlated with poor response to therapy and increased rates of death [48].…”

“…Plasma and serum levels of soluble immune checkpoints can change upon treatment with ICI, and in some cases, the magnitude of this change associates with clinical response. Three studies reported that sPD-L1 increased upon ICI therapy [81,84,89], while two observed sPD-L1 to remain constant upon ICI treatment (Table S1) [77,90]. In terms of clinical outcome, either a decrease or less of an increase in sPD-L1 upon treatment with ICI is correlated with improved clinical responses, with four studies (n = 204 patients) reporting similar findings (Table 2).…”

“…Elevated baseline sPD-L1 is associated with a poor clinical response to conventional therapies, with 29 different studies involving 3,200 cancer patients reporting a negative association with response rates, PFS or OS (Table 3). Specifically, among cancer patients treated with chemotherapy, higher baseline sPD-L1 levels correlated with shorter OS in those patients with NSCLC [46], gastric cancer [217,218], pancreatic cancer [219,220], urothelial cancer [81], and upper tract urothelial carcinoma [89]. As an example, in advanced gastric cancer patients receiving systemic chemotherapy, those with low sPD-L1 prior to therapy had both an improved OS (median: 8.9 months vs 14.6 months, p = 0.012, Fig.…”

Advances in the Treatment of Kidney and Upper Urinary Tract Cancers

“…This Special Issue aims to cover novel approaches in renal and urothelial cancers. We collected papers focused on novel approaches to urothelial cancers involving upper urinary tract and renal cancers that undertook original research focused on pre-clinical studies and biomarkers [ 9 , 10 , 11 , 12 ], prognostic models [ 13 , 14 , 15 ], the specific population of metastatic patients [ 16 ], and, finally, two narrative reviews [ 17 , 18 ].…”

“…A recent paper by Szeles et al [ 10 ] focused on the relevance of the circulating soluble levels (sPD-L1) of programmed death ligand-1 (PD-L1) in upper tract urothelial carcinoma (UTUC). The authors prospectively collected serum samples from 61 UTUC patients treated with radical nephroureterectomy (RNU), chemotherapy (CTX), or immune checkpoint inhibitor (ICI) therapy.…”