scholarly journals uPAR+ extracellular vesicles: a robust biomarker of resistance to checkpoint inhibitor immunotherapy in metastatic melanoma patients

2021 ◽  
Vol 9 (5) ◽  
pp. e002372
Author(s):  
Letizia Porcelli ◽  
Michele Guida ◽  
Simona De Summa ◽  
Roberta Di Fonte ◽  
Ivana De Risi ◽  
...  
Keyword(s):  
T Cell ◽  
Metastatic Melanoma ◽  
Clinical Outcomes ◽  
Immune Cell ◽  
Checkpoint Inhibitors ◽  
Progression Free Survival ◽  
Extracellular Vesicle ◽  
Lower Percentage ◽  
Kaplan Meier ◽  
Metastatic Sites

BackgroundEmerging evidence has highlighted the importance of extracellular vesicle (EV)-based biomarkers of resistance to immunotherapy with checkpoint inhibitors in metastatic melanoma. Considering the tumor-promoting implications of urokinase-type plasminogen activator receptor (uPAR) signaling, this study aimed to assess uPAR expression in the plasma-derived EVs of patients with metastatic melanoma to determine its potential correlation with clinical outcomes.MethodsBlood samples from 71 patients with metastatic melanoma were collected before initiating immunotherapy. Tumor-derived and immune cell-derived EVs were isolated and analyzed to assess the relative percentage of uPAR+ EVs. The associations between uPAR and clinical outcomes, sex, BRAF status, baseline lactate dehydrogenase levels and number of metastatic sites were assessed.ResultsResponders had a significantly lower percentage of tumor-derived, dendritic cell (DC)-derived and CD8+ T cell-derived uPAR +EVs at baseline than non-responders. The Kaplan-Meier survival curves for the uPAR+EV quartiles indicated that higher levels of melanoma-derived uPAR+ EVs were strongly correlated with poorer progression-free survival (p<0.0001) and overall survival (p<0.0001). We also found a statistically significant correlation between lower levels of uPAR+ EVs from both CD8+ T cells and DCs and better survival.ConclusionsOur results indicate that higher levels of tumor-derived, DC-derived and CD8+ T cell-derived uPAR+ EVs in non-responders may represent a new biomarker of innate resistance to immunotherapy with checkpoint inhibitors. Moreover, uPAR+ EVs represent a new potential target for future therapeutic approaches.

637 Immune-related adverse events (irAEs) may indicate a favorable prognosis in metastatic renal cell carcinoma (mRCC) patients treated with immune checkpoint inhibitors (ICI)

2020 ◽  
Vol 8 (Suppl 3) ◽  
pp. A672-A673
Author(s):  
Dylan Martini ◽  
Sean Evans ◽  
Subir Goyal ◽  
Yuan Liu ◽  
T Anders Olsen ◽  
...  
Keyword(s):  
Renal Cell Carcinoma ◽  
Overall Survival ◽  
Adverse Events ◽  
Clinical Outcomes ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Progression Free Survival ◽  
Free Survival ◽  
Kaplan Meier ◽  
Emory University

BackgroundImmune checkpoint inhibitors (ICI) have become an increasingly utilized treatment in metastatic renal cell carcinoma (mRCC). Although they have a favorable toxicity profile, immune-related adverse events (irAEs) can have a significant impact on patients‘ quality of life. It is not well understood whether irAEs are associated with improved clinical outcomes. We investigated the relationship between irAEs and clinical outcomes in mRCC patients treated with ICI.MethodsWe performed a retrospective study of 200 patients with mRCC who received ICI at Winship Cancer Institute of Emory University from 2015–2020. Clinical outcomes were measured by overall survival (OS), progression-free survival (PFS), and clinical benefit (CB). OS and PFS were calculated from ICI-initiation to date of death and radiographic or clinical progression, respectively. CB was defined as a best radiographic response of complete response (CR), partial response (PR), or stable disease (SD) for >6 months per response evaluation criteria in solid tumors (RECIST) version 1.1. Toxicity data was collected from clinic notes and laboratory values. The association with OS and PFS was modeled by Cox proportional hazards model. Kaplan-Meier curves were created for survival estimates.ResultsMost patients were males (71%), and 78% had clear-cell RCC (ccRCC). Most patients (58%) received anti-PD-1 monotherapy. The majority were international mRCC database consortium (IMDC) intermediate (57%) or poor-risk (26%). Anti-PD-1 monotherapy was the most common (58%) treatment regimen and most patients received ICI as first (38%) or second-line (42%) treatment. One-third of patients (33%) experienced an irAE, with the most common being endocrine (13%), gastrointestinal (11%), and dermatologic (10%). Patients who experienced irAEs had significantly longer OS (HR: 0.52, 95% CI: 0.32–0.87, p=0.013), higher chance of CB (OR: 2.10, 95% CI: 1.11–4.00, p=0.023) and showed a trend towards longer PFS (HR: 0.71, 95% CI: 0.49–1.02, p=0.065) in MVA (table 1). Patients who had thyroid irAEs had significantly longer OS, PFS, and higher chance of CB in MVA (table 1). The objective response rate was higher for patients who experienced irAEs (34% vs. 18%). Patients who experienced irAEs had significantly longer median OS (44.5 vs. 18.2 months, p=0.005) and PFS (7.5 vs 3.6 months, p=0.0028) compared to patients who did not (figure 1).Abstract 637 Table 1MVA* of association between irAEs and clinical outcomesAbstract 637 Figure 1Kaplan-Meier curves of association between immune-related adverse events (irAEs) and overall survival (OS, top panel) and progression-free survival (PFS, bottom panel)ConclusionsWe showed that mRCC patients who experienced irAEs, particularly thyroid irAEs, had improved clinical outcomes. This suggests that irAEs may be prognostic of favorable outcomes in mRCC patients treated with ICI. Larger, prospective studies are needed to validate these findings.AcknowledgementsResearch reported in this publication was supported in part by the Breen Foundation and the Biostatistics Shared Resource of Winship Cancer Institute of Emory University and NIH/NCI under award number P30CA138292. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.Trial RegistrationNot applicableEthics ApprovalThis retrospective study was approved by the Emory University Institutional Review Board.ConsentNot applicableReferencesNot applicable

Sequencing chemotherapy and immune checkpoint inhibitors (ICI) in metastatic urothelial carcinoma (UC): Meet-Uro1 study.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. e16013-e16013 ◽  
Author(s):  
Marco Bandini ◽  
Elena Farè ◽  
Daniele Raggi ◽  
Ugo De Giorgi ◽  
Giuseppe Luigi Banna ◽  
...  
Keyword(s):  
Cox Regression ◽  
Checkpoint Inhibitors ◽  
Single Agent ◽  
Objective Response ◽  
Progression Free Survival ◽  
Kaplan Meier ◽  
Metastatic Urothelial Carcinoma ◽  
Therapeutic Sequence ◽  
Multivariable Analyses ◽  
Metastatic Sites

e16013 Background: Several ICI are now approved in different therapeutic settings of metastatic UC. The identification of the optimal therapeutic sequence that includes standard chemotherapy (CT) use is a key objective of further research, mainly in the first-line (1L) setting. In this study, we analyzed the pathways of treatment post-ICI and focused on the effects of CT post-ICI in both 1L and salvage-line (≥2L) therapy of metastatic UC. Methods: Data from 15 Italian centers were collected. Patients (pts) should have received ICI in any line of treatment for metastatic UC and have experienced a disease progression (PD) according to RECIST 1.1. Cox regression analyses were performed within the subgroups, and adjusted Kaplan-Meier curves analyzed the progression-free survival (PFS) and overall survival (OS) post-ICI PD, according to the treatment line. Results: 278 pts (79 in 1L; 199 ≥2L) were analyzed. In total, after ICI, pts were treated with CT (N = 69), ICI beyond PD (N = 20) or no treatment (N = 189). Features associated with no therapy post-ICI were rapid PD on ICI (p < 0.001) and number of metastatic sites (p = 0.002). The objective response (OR) to CT post-ICI was 23.1% in 1L, and 18.5% in ≥2L. Median PFS was 5 months (m) in 1L and 3m ≥2L, median OS on CT was 13m in 1L and 9m ≥2L. Post-ICI CT was not significantly associated with improved OS in 1L on multivariable analyses (MVA): HR: 0.43 (95%CI: 0.15-1.23), but it was significant in MVA in ≥2L pts (HR: 0.22, 95%CI: 0.10-0.48). The type of previous ICI (combination-ICI vs single-agent ICI, p = 0.789), as well as the OR to previous ICI (p = 0.871) had no effect on OS with sequential CT on MVA. In the total population adjusted by line, median OS post-CT was 17m (range 15-NA), and with ICI beyond PD was 8m (6-NA) (p < 0.001). Conclusions: This large multicentric appraisal indicated that CT post-salvage ICI is endowed with similar activity and efficacy compared to ICI-naïve pts. Conversely, CT administered post-ICI in 1L determined less responses and was not significant on MVA. These effects are likely determined by the inability to rescue pts with rapidly aggressive disease. Shifting to salvage CT at the time of PD on ICI remains the preferable option in all suitable pts.

scholarly journals KLHL5 Is a Prognostic-Related Biomarker and Correlated With Immune Infiltrates in Gastric Cancer

2020 ◽  
Vol 7 ◽  
Author(s):  
Qiulin Wu ◽  
Guobing Yin ◽  
Jinwei Lei ◽  
Jiao Tian ◽  
Ailin Lan ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Clinical Outcomes ◽  
Immune Cell ◽  
Progression Free Survival ◽  
Differentially Expressed ◽  
Free Survival ◽  
Kaplan Meier ◽  
Patient Prognosis ◽  
The Relationship ◽  
Kaplan Meier Plotter

Background: KLHL5 (Kelch Like Family Member 5) is differentially expressed in gastric cancer, but its correlation with prognosis and functioning mechanism in gastric cancer remain unclear.Methods: The Oncomine database and TIMER were employed to appraise the KLHL5 expression in a variety of cancers. The correlation between KLHL5 expression and patient prognosis was extracted from the Kaplan–Meier plotter, GEPIA, and PrognoScan database. Then the relationship between KLHL5 expression and inflammatory infiltrate profiles was inquired by TIMER. Finally, GEPIA and TIMER were explored for the correlative significance between KLHL5 expression and immune cell–related marker sets.Results: KLHL5 was found to be differentially expressed and correlated with clinical outcomes in several types of cancers in the TCGA database. Especially, KLHL5 mRNA expression was upregulated and correlated with poorer overall survival and progression-free survival in gastric cancer. Moreover, elevated KLHL5 expression was significantly related with patient node stage, infiltration level, and expression of multiple immune marker sets.Conclusions: These results implicate that KLHL5 expression is closely linked with patient clinical outcomes and the microenvironmental infiltration level in different neoplasms. This indicates that KLHL5 is a modulator in infiltrate recruitment, shaping the landscape of immune cell infiltration. Thus, it represents an eligible prognostic predictor for gastric malignancy.

241 Clinical outcomes of metastatic melanoma patients with liver metastases treated with anti-PD-1 monotherapy versus combination ipilimumab/nivolumab

2020 ◽  
Vol 8 (Suppl 3) ◽  
pp. A259-A260
Author(s):  
Vincent Ma ◽  
Kent Griffith ◽  
Jessica Waninger ◽  
Stephanie Daignault-Newton ◽  
Leslie Fecher ◽  
...  
Keyword(s):  
Overall Survival ◽  
Liver Metastases ◽  
Metastatic Melanoma ◽  
Clinical Outcomes ◽  
Progression Free Survival ◽  
Forest Plot ◽  
Advanced Stage ◽  
Free Survival ◽  
Kaplan Meier ◽  
Melanoma Patients

BackgroundRecent studies report of liver metastases (LM) as a poor prognostic factor in patients treated with immune checkpoint inhibitors (ICIs),1 but clinical outcomes associated with different ICI regimens remains uncertain. In this study, we investigate melanoma patients with and without LM and assess differential treatment outcomes associated with anti-PD-1 monotherapy and combination ipilimumab/nivolumab (I/N).MethodsWe conducted a single-center, retrospective review of advanced stage melanoma patients with and without LM treated with anti-PD-1 monotherapy (nivolumab or pembrolizumab) or I/N between 2012 and 2018. Overall survival (OS) and progression free survival (PFS) were measured from the first dose of treatment to date of death and clinical or radiographic progression, respectively. Univariate and multivariate analysis were performed using Cox proportional hazard (CPH) models and logistic regression models. Inverse probability of treatment weighting using propensity scores in CPH models was used to account for the following baseline covariates: age, ECOG performance status, BRAF status, pre-treatment LDH level, prior therapy status, and number and sites of metastases.Results327 patients were identified, 87 with LM and 240 without LM. Patients with LM was associated with worse PFS [HR: 2.1, 95% CI, 1.5 – 3.1] (figure 1) and OS [HR: 3.4, 95% CI, 2.2 – 5.2] (figure 2). Respective 3-year PFS and OS estimates associated with anti-PD-1 monotherapy were 21.8% and 28.7% in patients with LM (figure 3, figure 4); and 36.5% and 57.6% without LM (figure 5, figure 6). Respective 3-year PFS and OS estimates associated with I/N were 46.7% and 56.7% in patients with LM; and 58.0% and 74.4% without LM.Abstract 241 Figure 1Forest plot for progression free survival in all advanced stage (unresectable or metastatic) melanoma patients treated with anti-PD-1 monotherapy (nivolumab or pembrolizumab) or combination ipilimumab/nivolumab (Ipi/Nivo). n = 327Abstract 241 Figure 2Forest plot for overall survival in all advanced stage (unresectable or metastatic) melanoma patients treated with anti-PD-1 monotherapy (nivolumab or pembrolizumab) or combination ipilimumab/nivolumab (Ipi/Nivo). n = 327Abstract 241 Figure 3Kaplan-Meier curves comparing advanced stage melanoma patients with liver metastases treated with anti-PD-1 monotherapy (nivolumab or pembrolizumab) versus ipilimumab/nivolumab by progression free survival. n = 87Abstract 241 Figure 4Kaplan-Meier curves comparing advanced stage melanoma patients with liver metastases treated with anti-PD-1 monotherapy (nivolumab or pembrolizumab) versus ipilimumab/nivolumab by overall survival. n = 87Abstract 241 Figure 5Kaplan-Meier curves comparing advanced stage melanoma patients without liver metastases treated with anti-PD-1 monotherapy (nivolumab or pembrolizumab) versus ipilimumab/nivolumab by progression free survival. n = 240Abstract 241 Figure 6Kaplan-Meier curves comparing advanced stage melanoma patients without liver metastases treated with anti-PD-1 monotherapy (nivolumab or pembrolizumab) versus ipilimumab/nivolumab by overall survival. n = 240ConclusionsIn melanoma patients treated with PD-1 inhibitor-based regimens, the presence of LM leads to poorer survival outcomes. Our study suggests the poor prognosis associated with LM can be substantially mitigated by treatment with combination I/N over anti-PD-1 monotherapy. Further studies are warranted to investigate the anti-immunotherapy effect associated with LM.Ethics ApprovalThe study was approved by the University of Michigan institutional ethical guidelines and patients‘ consents were waived following Institutional Review Board protocol review (HUM00156014).ReferenceBilen MA, Shabto JM, Martini DJ, et al. Sites of metastasis and association with clinical outcome in advanced stage cancer patients treated with immunotherapy. BMC Cancer 2019; 19(1):857.

scholarly journals No Impact of NRAS Mutation on Features of Primary and Metastatic Melanoma or on Outcomes of Checkpoint Inhibitor Immunotherapy: An Italian Melanoma Intergroup (IMI) Study

Cancers ◽  
2021 ◽  
Vol 13 (3) ◽  
pp. 475
Author(s):  
Michele Guida ◽  
Nicola Bartolomeo ◽  
Pietro Quaglino ◽  
Gabriele Madonna ◽  
Jacopo Pigozzo ◽  
...  
Keyword(s):  
Metastatic Melanoma ◽  
Checkpoint Inhibitor ◽  
Progression Free Survival ◽  
Nras Mutation ◽  
Disease Free Interval ◽  
Free Survival ◽  
Mutational Status ◽  
Metastatic Sites ◽  
Disease Free ◽  
Mutant Braf

Aims: It is debated whether the NRAS-mutant melanoma is more aggressive than NRAS wildtype. It is equally controversial whether NRAS-mutant metastatic melanoma (MM) is more responsive to checkpoint inhibitor immunotherapy (CII). 331 patients treated with CII as first-line were retrospectively recruited: 162 NRAS-mutant/BRAF wild-type (mut/wt) and 169 wt/wt. We compared the two cohorts regarding the characteristics of primary and metastatic disease, disease-free interval (DFI) and outcome to CII. No substantial differences were observed between the two groups at melanoma onset, except for a more frequent ulceration in the wt/wt group (p = 0.03). Also, the DFI was very similar in the two cohorts. In advanced disease, we only found lung and brain progression more frequent in the wt/wt group. Regarding the outcomes to CII, no significant differences were reported in overall response rate (ORR), disease control rate (DCR), progression free survival (PFS) or overall survival (OS) (42% versus 37%, 60% versus 59%, 12 (95% CI, 7–18) versus 9 months (95% CI, 6–16) and 32 (95% CI, 23–49) versus 27 months (95% CI, 16–35), respectively). Irrespectively of mutational status, a longer OS was significantly associated with normal LDH, <3 metastatic sites, lower white blood cell and platelet count, lower neutrophil-to-lymphocyte (N/L) ratio. Our data do not show increased aggressiveness and higher responsiveness to CII in NRAS-mutant MM.

671 Update of a systematic review and meta-analysis studying the association between antibiotic use and clinical outcomes of non-small-cell lung cancer patients treated with immune checkpoint inhibitors

2020 ◽  
Vol 8 (Suppl 3) ◽  
pp. A708-A708
Author(s):  
Pierre-Alain Bandinelli ◽  
Julie Cervesi ◽  
Clément Le Bescop ◽  
Renaud Buffet ◽  
Jean De Gunzburg ◽  
...  
Keyword(s):  
Systematic Review ◽  
Clinical Outcomes ◽  
Time Window ◽  
Checkpoint Inhibitors ◽  
Meta Analysis ◽  
Progression Free Survival ◽  
Antibiotic Use ◽  
Forest Plot ◽  
Antibiotic Exposure ◽  
Hazard Ratios

BackgroundImmune checkpoint inhibitors (ICIs) have been shown to improve patients‘ clinical outcomes in a variety of cancers, but with variable efficacy. Prior research has also suggested that systemic antibiotic (ABX) exposure may impact the intestinal microbiota and result in suboptimal ICI treatment outcomes. Our team published a systematic review and meta-analysis showing that ABX use could indeed decrease the survival of patients diagnosed with non-small-cell lung cancer (NSCLC) and treated with ICIs.1 The present abstract aims at updating this meta-analysis by incorporating new studies that have been published in the period ranging from September 2019 to August 2020.MethodsMedline (through PubMed), the Cochrane Library and major oncology conferences proceedings were systematically searched to identify studies assessing the impact of ABX use on the clinical outcomes of NSCLC patients treated with ICIs. Studies were found eligible for inclusion when they mentioned a hazard ratio (HR) or Kaplan–Meier curves for overall survival (OS) or progression-free survival (PFS) based on antibiotic exposure. Pooled HRs for OS and PFS and HRs for OS and PFS according to different time windows for ABX exposure were calculated.Results6 eligible new studies were identified between September 2019 and August 2020 while 3 other studies were updated with new information. Altogether, 27 studies reported data for OS (6,436 patients, 826 of whom coming from new studies) and 24 for PFS (3,751 patients, 786 of whom coming from new studies). The pooled HR was 1.75 (95% confidence interval [CI]: 1.38–2.23) for OS and 1.57 (95% CI: 1.28–1.92) for PFS, confirming a significantly reduced survival in patients with NSCLC exposed to ABX. The detailed analysis in subgroups based on the time window of exposure (figure 1, figure 2) suggests that the deleterious effect of ABX is stronger when the exposition happens shortly before and after the initiation of the ICI treatment.Abstract 671 Figure 1Forest plot of hazard ratios for overall survival of patients diagnosed with NSCLC and exposed to antibiotics versus not exposed to antibiotics, according to the time window of antibiotic exposureAbstract 671 Figure 2Forest plot of hazard ratios for progression-free survival of patients diagnosed with NSCLC and exposed to antibiotics versus not exposed to antibiotics, according to the time window of antibiotic exposureConclusionsThe update of the meta-analysis confirms the previously reported deleterious effect of ABX on ICI treatment outcomes, taking into account the latest publications in the field. The topic deserves further research to uncover if the effect will stand with 1st line use of ICI together with chemotherapies and/or other approved combinations, elucidate the mechanisms at stake and improve care of patients.ReferencesLurienne L, Cervesi J, Duhalde L, de Gunzburg J, Andremont A, Zalcman G, et al. NSCLC immunotherapy efficacy and antibiotic use: a systematic review and meta-analysis. J Thorac Oncol 2020;15:1147–1159.

scholarly journals Clinical Outcomes of Metastatic Melanoma Treated With Checkpoint Inhibitors and Multisite Radiotherapy

2017 ◽  
Vol 153 (10) ◽  
pp. 1056 ◽  
Author(s):  
Jérôme Doyen ◽  
Alexandra Picard ◽  
Arash O. Naghavi ◽  
Antoine Thyss ◽  
Thierry Passeron ◽  
...  
Keyword(s):  
Metastatic Melanoma ◽  
Clinical Outcomes ◽  
Checkpoint Inhibitors

scholarly journals Peripheral T cell receptor diversity is associated with clinical outcomes following ipilimumab treatment in metastatic melanoma

2015 ◽  
Vol 3 (1) ◽  
Author(s):  
Michael A. Postow ◽  
Manuarii Manuel ◽  
Phillip Wong ◽  
Jianda Yuan ◽  
Zhiwan Dong ◽  
...  
Keyword(s):  
T Cell ◽  
Metastatic Melanoma ◽  
Clinical Outcomes ◽  
T Cell Receptor ◽  
Cell Receptor

scholarly journals Dynamical Systems Modeling of Early-Term Immune Reconstitution with Different Anti-Thymocyte Globulin (ATG) Administration Schedules in Allogeneic Stem Cell Transplantation.

2021 ◽  
Author(s):  
Viktoriya Zelikson ◽  
Amir Ahmed Toor ◽  
Gary Simmons ◽  
Natasha Raman ◽  
Elizabeth Krieger ◽  
...  
Keyword(s):  
T Cell ◽  
Clinical Outcomes ◽  
Cell Transplantation ◽  
Immune Reconstitution ◽  
Cellular Therapy ◽  
Immune Cell ◽  
Chronic Gvhd ◽  
T Cell Response ◽  
Cell Recovery ◽  
Early Term

Alloreactivity forms the basis of allogeneic hematopoietic cell transplantation (HCT), with donor derived T cell response to recipient antigens mediating clinical responses either in part or entirely. These encompass the different manifestations of graft vs. host disease (GVHD), infection risk as well as disease response. Whilst the latter is contingent upon disease biology and thus may be less predictable, the former two are more likely to be directly proportional to the magnitude of donor derived T cell recovery. Herein we explore the quantitative aspects of immune cell recovery following allogeneic HCT and clinical outcomes in two cohorts of HLA matched allograft recipients who received rabbit anti-thymocyte globulin (ATG) on different schedules (days -9 to -7 vs. -3 to -1). Monocyte as well as donor derived T cell (ddCD3) recovery was superior in those given ATG early in their course (days -9/-7). This difference was related to a more rapid rate of ddCD3 recovery, largely driven by CD3+/8+ cells in the first month following transplantation. Early monocyte recovery was associated with later T cell recovery, improved survival, and less chronic GVHD. In contrast rapid and early ddCD3 expansion out of proportion to monocyte recovery was associated with a high likelihood of acute GVHD and poor survival. This analytic methodology demonstrates that modeling 'early-term immune reconstitution' following HCT yields insights that may be useful in management of post-transplant immunosuppression and adaptive cellular therapy to optimize clinical outcomes.

scholarly journals The Change of Soluble Programmed Cell Death-Ligand 1 (sPD-L1) in Glioma Patients Receiving Radiotherapy and Its Impact on Clinical Outcome

2020 ◽  
Author(s):  
Xing-chen Ding ◽  
Liang-liang Wang ◽  
Yu-fang Zhu ◽  
Jia Yang ◽  
Jin-ming Yu ◽  
...  
Keyword(s):  
Checkpoint Inhibitors ◽  
Progression Free Survival ◽  
Enzyme Linked Immunosorbent Assay ◽  
Murine Models ◽  
Isocitrate Dehydrogenase 1 ◽  
Ki 67 ◽  
Kaplan Meier ◽  
Programmed Death ◽  
Potential Biomarker ◽  
Before And After

Abstract Background: It has been proved that the levels of soluble programmed death-ligand 1 (sPD-L1) are associated with prognosis in extracranial malignancies. However, the expression of sPD-L1 in glioma patients receiving radiotherapy (RT) still remains unclear.The purpose of this study is to evaluate the concentration of sPD-L1in the plasma of glioma patients before and after RT, and to explore its relationship with clinical outcomes.Methods: Between October 2017 and September 2018, the glioma patients treated with RT (30 ± 10 Gy, 2 Gy/f) were enrolled and the blood samples were collected before and after RT. We quantified the sPD-L1 levels by enzyme-linked immunosorbent assay (ELISA). The isocitrate dehydrogenase-1 (IDH-1) promoter status and Ki-67 expression were evaluated by immunohistochemistry. The murine models of glioma were used to address whether circulating sPD-L1 molecules are directly targeted by the anti-PD-L1 antibody. The associations between sPD-L1 and clinical features were assessed with Pearson or Spearman correlation. The progression-free survival (PFS) and overall survival (OS) were determined by Kaplan-Meier method.Results: Sixty glioma patients were included, with the median age 52-year-old. The proportion of grade I, II, III, IV were 6.7%, 23.3%, 28.4% and 41.6%, respectively. The baseline sPD-L1 levels were significantly associated with tumor grades, IDH-1 mutation status and Ki-67 expression. Using 14.35 pg/mL as the cutoff, significantly worse PFS and OS were both observed in patients with higher baseline level of sPD-L1 (P = 0.027, 0.008, respectively). RT significantly increased the mean level of sPD-L1 (P < 0.001). Further analysis showed that increased level of sPD-L1 in IDH-1 mutation patients was higher than that in wide-type ones. Furthermore, the murine models of glioma indicate that sPD-L1 can be blocked by anti-PD-L1 antibody. Conclusion: This study reported that sPD-L1 might be a potential biomarker to predict the outcome in glioma receiving RT. The elevated level of sPD-L1 after RT suggested that the strategy of combination with immune checkpoint inhibitors and RT might be promising for glioma, especially for patients with IDH-1 mutation.

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