Introduction Immune checkpoint inhibitors (ICI) such as anti-PD-L1 and anti-PD-1 agents have been proven to be effective in various cancers. However, the rate of non-responders is still high in all cancer entities. Therefore, the identification of biomarkers that could help to optimize therapeutic decision-making is of great clinical importance. Soluble PD-L1 (sPD-L1) and PD-1 (sPD-1) are emerging blood-based biomarkers and were previously shown to be prognostic in various clinical studies. Objective We aimed to evaluate the prognostic relevance of sPD-L1 and sPD-1 in patients with different tumor entities who underwent ICI therapy. Methods We searched for articles in PubMed via Medline, Embase, Scopus, and Cochrane databases. The primary outcome was overall survival (OS) and progression-free survival (PFS); furthermore, we analyzed on-treatment serum level changes of sPD-L1 and sPD-1 during ICI therapy. Results We synthesized the data of 1,054 patients with different cancer types from 15 articles. Pooled univariate analysis showed that elevated levels of sPD-L1 were significantly associated with inferior OS (HR = 1.67; CI:1.26–2.23, I2 = 79%, p < 0.001). The strongest association was found in non-small cell lung cancer, whereas weaker or no association was observed in melanoma as well as in renal cell and esophageal cancers. Pooled multivariate analysis also showed that elevated levels of sPD-L1 correlated with worse OS (HR = 1.62; CI: 1.00–2.62, I2 = 84%, p = 0.05) and PFS (HR = 1.71; CI:1.00–2.94, I2 = 82%, p = 0.051). Furthermore, we observed that one or three months of anti-PD-L1 treatment caused a strong (27.67-fold) elevation of sPD-L1 levels in malignant mesothelioma and urothelial cancer. Conclusions We found significantly inferior OS in ICI-treated cancer patients with elevated pre-treatment sPD-L1 levels, but this association seems to be tumor type dependent. In addition, sPD-L1 increases during anti-PD-L1 therapy seems to be therapy specific.

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Upper tract urothelial carcinoma (UTUC) is a rare cancer with a barely predictable clinical behaviour. Serum MMP-7 is a validated prognostic marker in urothelial bladder cancer, a tumour entity with large clinical, histological, and molecular similarity to UTUC. The serum MMP-7 levels have not yet been investigated in UTUC. In the present study, we determined MMP-7 concentrations in an overall number of 103 serum samples from 57 UTUC patients who underwent surgical or systemic (platinum or immune checkpoint inhibitor) therapy by using the ELISA method. In addition to pre-treatment samples, the serum samples collected at predefined time points after or during therapy were also investigated. Serum MMP-7 concentrations were correlated with clinicopathological and follow-up data. Our results revealed significantly, two-fold elevated pre-treatment serum MMP-7 levels in metastatic cases of UTUC in both the radical surgery- and the chemotherapy-treated cohorts (p = 0.045 and p = 0.040, respectively). In addition, high serum MMP-7 levels significantly decreased after radical surgery, and high pre-treatment MMP-7 concentrations were associated with shorter survival both in the surgery- and chemotherapy-treated cohorts (p = 0.029 and p = 0.001, respectively). Our results revealed pre-treatment serum MMP-7 as a prognostic marker for UTUC, which may help to improve preoperative risk-stratification and thereby improve therapeutic decision-making.

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.

Absztrakt: Bevezetés: Urothelium béleli a vesemedencét, a húgyvezetéket, a húgyhólyagot és a húgycső proximalis harmadát, így ezen területek bármelyikén kialakulhat átmeneti sejtes carcinoma. A felső üregrendszeri daganatok ritka elváltozások, jelentőségüket azonban az adja, hogy a húgyhólyagban gyakori a recidíva, mely kockázatának felmérésére a mai napig nem alakult ki egységesen elfogadott rizikóbecslés. Célkitűzés: A felső üregrendszeri daganatos betegek adatainak általános jellemzése, illetve a húgyhólyag-recidívára vonatkozó rizikóbecslés. Módszer: A 2005. január 1. és 2016. december 31. közötti időszakban a Semmelweis Egyetem Urológiai Klinikáján radikális ureteronephrectomiával kezelt betegek adatainak tanulmányozása, statisztikai elemzése. Eredmények: Átmeneti sejtes felső üregrendszeri daganat 135 betegnél igazolódott. A betegeket a műtéttől számítva átlagosan 32 hónapig (SD: 30,25) követték, ezalatt 31 betegnél (23%) találtak húgyhólyag-recidívát, átlagosan 19,6 hónap (SD: 29,7) után. Minél idősebb korban fedezték fel a betegnél a primer daganatot, annál hamarabb észleltek kiújulást a húgyhólyagban (p = 0,007). A diagnóziskor ismert magas vérnyomás esetén is szignifikánsan korábban tért vissza az elváltozás (p = 0,035). Következtetés: A vizsgálat eredményei alapján az idősebb és multimorbid betegek esetében a daganat hamarabb recidivált a húgyhólyagban, ezért az ő figyelmüket különösen érdemes felhívni a rendszeres, cystoscopiát is magában foglaló ellenőrző vizsgálat fontosságára már a kezelés megkezdésekor. Orv Hetil. 2020; 161(21): 881–888.