Mutually exclusive expression of CD73 and PDL1 in tumors from patients (pt) with NSCLC, gastroesophageal (GE) and urothelial bladder carcinoma (UBC).

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. 3079-3079 ◽  
Author(s):  
Philip Martin ◽  
Andreas Spitzmueller ◽  
Song Wu ◽  
Moritz Widmaier ◽  
RENE KORN ◽  
...  
Keyword(s):  
Immune Evasion ◽  
Meta Analysis ◽  
High Expression ◽  
Cd8 Cells ◽  
Urothelial Bladder Carcinoma ◽  
Programmed Death ◽  
Urothelial Bladder ◽  
Programmed Death 1 ◽  
Cd73 Expression ◽  
Anti Tumor Activity

3079 Background: Tumors use multiple means of immune evasion, notably the programmed death-1 (PD1)/PDL1 pathway. Anti-PD1/PDL1 therapy induces anti-tumor activity and has improved pt outcomes. Activation of the immunosuppressive CD39/CD73/adenosine pathway might play a role in pts who do not benefit from anti-PD1/PDL1 therapies. We evaluated expression of CD73 and PDL1 and explored the association between CD73 and intraepithelial (IE) CD8+ cells (TILs) to begin to understand their potential interplay in cancer. Methods: Immunohistochemistry for PDL1, CD73 and CD8 was conducted on tumors of non-squamous NSCLC (NSq) (n=42), GE (n=50), and UBC (n=50). PDL1 and CD73 were scored by image analysis with Definiens software. IE CD8+ TILs were scored semi-quantitatively by a pathologist (0-2 = low; 3-4 = high). Using the top tertile of PDL1 and CD73 for high expression levels, a Fisher’s meta-analysis was calculated across the three indications. Results: Across all tumors, 25% (35/142) were PDL1 high (+), but CD73 low (-) and another 25% (35/142) were CD73+ but PDL1- (p=0.06, see table). This trend for mutually exclusive high expression of PDL1/CD73 was strongest in GE (p<0.01). In the PDL1+ group 76% (35/46) had high IE CD8+ TILs whereas in the CD73+ group only 35% (16/46) had high TILs (p<0.0001 using a proportions test). In the PDL1+/CD73- pt subset 77% (27/35) were CD8+ high vs only 23% (8/35) in the PDL1-/CD73+ subset. Conclusions: The identification of distinct pt subsets based on high PDL1 and/or CD73 expression suggests that tumors have multiple mechanisms of immune evasion. Increased IE CD8+ TILs were associated with PDL1 expression. The finding that PDL1-/ CD73+ tumors have lower IE CD8+ TILs compared to PDL1+/CD73- tumors suggests a role for CD73 in excluding IE TILs. Larger sample sets are needed to confirm these findings and to further explore any relationship with the tumor microenvironment. Our data suggests potential approaches to identify subsets of pts likely to benefit from immunotherapy targeting PDL1 and CD73. [Table: see text]

scholarly journals PD-1/PD-L1 Immune Checkpoint Inhibitors after Platinum-based Chemotherapy in Metastatic or Locally Advanced Urothelial Bladder Carcinoma: A Systematic Review and Meta-analysis

2021 ◽  
Author(s):  
Thara Tunthanathip ◽  
Tanan Bejrananda
Keyword(s):  
Systematic Review ◽  
Overall Survival ◽  
Cell Death ◽  
Bladder Carcinoma ◽  
Meta Analysis ◽  
Locally Advanced ◽  
Second Line ◽  
Urothelial Bladder Carcinoma ◽  
Urothelial Bladder ◽  
Line Chemotherapy

Objective: This study aimed to assess the effect of anti-programmed cell death-1/programmed cell death-ligand-1 (PD-1/PD-L1) agents compared with second-line therapy in patients with metastatic or locally advanced urothelial bladder carcinoma following previous platinum-containing chemotherapy.Material and Methods: We systematically searched three electronic databases. The protocol of the study was registered in Prospero (CRD42019142494). Using the Grading of Recommendations Assessment, Development, and Evaluation approach, the certainty of evidence (CoE) was estimated.Results: The search results initially found 8168 publications. For qualitative synthesis, two publications were included. Pooled results indicated that patients treated with anti-PD-1/PD-L1 agents had significantly prolonged overall survival (hazard ratio (HR) 0.80; 95% confidence interval (CI) 0.7-0.9; I2 21.0%; moderate CoE). According to positive PD-L1 expression, PD-1/PD-L1 inhibitors had significantly more survival than chemotherapy (HR 0.75; 95% CI 0.5-0.9, I2 57.0%, low CoE). Furthermore, there was no significant difference in adverse events (AE) between the anti-PD-1/PDL1 agents and second-line chemotherapy (risk ratio 0.68; 95% CI 0.3-1.4; I2 97.0%, low CoE).Conclusion: The present meta-analysis and systematic review provide strong evidence that anti-PD-1/PD-L1 agents could improve overall survival and have similar results in AEs compared with second-line chemotherapy. Further studies will confirm the power of immunotherapy for the treatment of metastatic or locally advanced urothelial bladder carcinoma.

scholarly journals αvβ3-integrin regulates PD-L1 expression and is involved in cancer immune evasion

2019 ◽  
Vol 116 (40) ◽  
pp. 20141-20150 ◽  
Author(s):  
Andrea Vannini ◽  
Valerio Leoni ◽  
Catia Barboni ◽  
Mara Sanapo ◽  
Anna Zaghini ◽  
...  
Keyword(s):  
Immune Evasion ◽  
Αvβ3 Integrin ◽  
Primary Tumors ◽  
Effective Strategies ◽  
Immune Mediated ◽  
Programmed Death ◽  
Programmed Death 1 ◽  
Β3 Integrin ◽  
Immunotherapy Target ◽  
Immunosuppressive Microenvironment

Tumors utilize a number of effective strategies, including the programmed death 1/PD ligand 1 (PD-1/PD-L1) axis, to evade immune-mediated control of their growth. PD-L1 expression is mainly induced by IFN receptor signaling or constitutively induced. Integrins are an abundantly expressed class of proteins which play multiple deleterious roles in cancer and exert proangiogenic and prosurvival activities. We asked whether αvβ3-integrin positively regulates PD-L1 expression and the anticancer immune response. We report that αvβ3-integrin regulated constitutive and IFN-induced PD-L1 expression in human and murine cancerous and noncancerous cells. αvβ3-integrin targeted STAT1 through its signaling C tail. The implantation of β3-integrin–depleted tumor cells led to a dramatic decrease in the growth of primary tumors, which exhibited reduced PD-L1 expression and became immunologically hot, with increased IFNγ content and CD8+ cell infiltration. In addition, the implantation of β3-integrin–depleted tumors elicited an abscopal immunotherapeutic effect measured as protection from the challenge tumor and durable splenocyte and serum reactivity to B16 cell antigens. These modifications to the immunosuppressive microenvironment primed cells for checkpoint (CP) blockade. When combined with anti–PD-1, β3-integrin depletion led to durable therapy and elicited an abscopal immunotherapeutic effect. We conclude that in addition to its previously known roles, αvβ3-integrin serves as a critical component of the cancer immune evasion strategy and can be an effective immunotherapy target.

PD-L1 Positivity Associated With Presence of Tertiary Lymphoid Structures and High-Stage Disease in Upper Tract Urothelial Carcinoma

2020 ◽  
Vol 154 (6) ◽  
pp. 802-810
Author(s):  
Maria E Smith ◽  
Sahar J Farahani ◽  
Timothy Chao ◽  
Matthew Palmer ◽  
Aileen Arriola ◽  
...  
Keyword(s):  
Urothelial Carcinoma ◽  
Upper Tract Urothelial Carcinoma ◽  
Upper Tract ◽  
Urothelial Bladder Carcinoma ◽  
Stage Disease ◽  
Programmed Death ◽  
Persistent Antigen ◽  
Urothelial Bladder ◽  
Tertiary Lymphoid Structures ◽  
Lymphoid Structures

Abstract Objectives Persistent antigen exposure leads to the accumulation of lymphocytes and subsequent tertiary lymphoid structures (TLS). We investigated the relationship of tumor microenvironment (TME) with respect to programmed death ligand 1 (PD-L1), its receptor programmed death 1 (PD-1), and TLS in upper tract urothelial carcinoma (UTUC) cases and compared them with UTUC associated with urothelial bladder carcinoma (UTUC-BCa). Methods We retrospectively identified 72 patients with UTUC. Representative slides were reviewed, and TLS were counted. Immunohistochemical stains for PD-1 and PD-L1 were performed. PD-1–positive lymphocytes were counted and H-score for PD-L1–positive membranous staining was determined. Results PD-L1 expression in the tumor was present in 55.1% of the UTUC cases. Higher stage was associated with increased PD-L1 expression (P = .035). TLS were present in 33.3% and their presence was significantly associated with PD-L1 positivity (P = .024). This association remained significant after adjustment for UTUC-BCa. TLS were also associated with a greater number of infiltrating PD-1-positive lymphocytes (P = .013). Conclusions This study is one of the first comparative studies of the TME in UTUC and UTUC-BCa. PD-L1 is expressed in a subset of UTUC and is associated with TLS. The presence of TLS is an inherent characteristic of UTUC and not secondary to the presence of BCa.

scholarly journals The Efficacy and Safety of Programmed Death-1 and Programmed Death Ligand 1 Inhibitors for the Treatment of Hepatocellular Carcinoma: A Systematic Review and Meta-Analysis

2021 ◽  
Vol 11 ◽  
Author(s):  
Shukang He ◽  
Weichao Jiang ◽  
Kai Fan ◽  
Xiaobei Wang
Keyword(s):  
Hepatocellular Carcinoma ◽  
Group Treatment ◽  
Checkpoint Inhibitors ◽  
Meta Analysis ◽  
Cochrane Library ◽  
Control Group ◽  
Efficacy And Safety ◽  
Programmed Death Ligand 1 ◽  
Programmed Death ◽  
Programmed Death 1

BackgroundHepatocellular carcinoma (HCC) is often diagnosed at an advanced stage where only systemic treatment can be offered. The emergence of immune checkpoint inhibitors (ICIs) provides hope for the treatment of HCC. In this study, we performed a meta-analysis to provide evidence for the efficacy and safety of ICIs in the treatment of HCC.MethodsThe following databases and websites were searched: Embase, PubMed, Cochrane Library and ClinicalTrials.gov. The primary endpoints were response rate (RR), disease control rate (DCR), progression-free survival (PFS) and overall survival (OS).ResultsFinally, twelve studies were included in this meta-analysis. When the corresponding outcome indicators and their 95% confidence intervals (CIs) were pooled directly, the overall RR, DCR, PFS and OS were 0.17 (0.15-0.19, I2 = 56.2%, P=0.009), 0.58 (0.55-0.61, I2 = 75.9%, P&lt;0.001), 3.27 months (2.99-3.55, I2 = 73.0%, P=0.001), 11.73 months (10.79-12.67, I2 = 90.3%, P&lt;0.001). Compared to the control group, treatment with ICIs significantly improved RR, PFS and OS, the OR and HRs were 3.11 (2.17-4.44, P&lt;0.001), 0.852 (0.745-0.974, P=0.019) and 0.790 (0.685-0.911, P=0.001), respectively. However, no significant improvement in DCR was found in ICIs treatment in this meta-analysis.ConclusionHCC patients would benefit from ICIs treatment, however, more studies are needed in the future to provide more useful evidence for the treatment of HCC by programmed death-1 (PD-1) or programmed death ligand 1 (PD-L1) inhibitors.

Incidence and risk of colitis with programmed death-1 versus programmed death-ligand 1 inhibitors for the treatment of cancer.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. e15087-e15087
Author(s):  
Hirotaka Miyashita ◽  
Takahisa Mikami ◽  
Sera Satoi ◽  
Christina Cruz ◽  
Matt D. Galsky
Keyword(s):  
Adverse Event ◽  
Relative Risk ◽  
Fixed Effects ◽  
Meta Analysis ◽  
Programmed Death Ligand 1 ◽  
Programmed Death ◽  
Significant Difference ◽  
Programmed Death 1 ◽  
Grade 3 ◽  
Meta Analyses

e15087 Background: Programmed death 1 (PD-1) inhibitors and Programmed Death-Ligand 1 (PD-L1) inhibitors are immune checkpoint inhibitors (ICIs) approved for treatment of several different cancers. Colitis is a major immune-related adverse event associated with ICIs, but the risk of colitis with PD-1 versus PD-L1 inhibitors is not well characterized. Methods: We performed a meta-analysis for the incidence of all grade and grade 3-4 colitis with PD-1 inhibitor (nivolumab, pembrolizumab, and cemiplimab) or PD-L1 inhibitor (atezolizumab, avelumab, and durvalumab) monotherapy using a fixed effects model. We also conducted subgroup meta-analyses of non-small cell lung cancer (NSCLC) or urothelial carcinoma (UC) trials, and a network meta-analysis of randomized trials comparing PD-1 or PD-L1 inhibitors with docetaxel for NSCLC. We analyzed Food and Drug Administration Adverse Event Reporting System (FAERS) database to estimate the reporting odds ratio (ROR) of each medication, which provides the estimated relative risk most valid in spontaneous report database. Results: We identified 88 studies that met inclusion for the analysis. PD-1 inhibitors were associated with higher incidence of all grade and grade 3-4 colitis compared to PD-L1 inhibitors in the analysis of all cancer types (1.49% vs 0.83%, relative risk (RR); 1.80, 95% confidence interval (CI); 1.22-2.67 for all grade colitis, and 0.85% vs 0.34%, RR; 2.52, 95% CI; 1.46-4.37 for grade 3-4 colitis). The meta-analyses on NSCLC and UC, and the network meta-analysis on NSCLC also showed the tendency that PD-1 inhibitors are associated with higher risk of all grade and grade 3-4 colitis, though only the analysis on UC for all grade colitis showed a significant difference. (1.95% vs 0.64%, RR; 3.05, 95% CI; 1.18 - 7.88) Retrospective analysis showed ROR of 16.78 (95% CI; 15.8-17.8) for PD-1 inhibitors, and 12.93 (95% CI; 10.74-15.42) for PD-L1 inhibitors. We found that ROR of PD-1inhibitors was 1.17 (95% CI; 0.97-1.43) compared to PD-L1 inhibitors. Conclusions: Our study showed that PD-1 inhibitors have higher risk of colitis than PD-L1 inhibitors.

Number of PD-1+/CD8+ Cells in Peripheral Blood of Patients with Lymphoma Reflects Tumor Burden, Lymphoma Subtype, Disease Phase and Is Significantly Higher Compared to Healthy Volunteers.

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 2670-2670
Author(s):  
Vit Prochazka ◽  
Martin Novák ◽  
Zuzana Pikalova ◽  
Tomas Papajik ◽  
Karel Indrak ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Healthy Volunteers ◽  
Peripheral Blood ◽  
Healthy Subjects ◽  
Cd4 Cells ◽  
Cd8 Cells ◽  
Programmed Death ◽  
Programmed Death 1 ◽  
Disease Stages

Abstract Abstract 2670 Background: Programmed death-1 (PD-1) and programmed death-1 ligand (PD-L) signaling pathways are involved in the functional impairment and “exhaustion” of cytotoxic CD8+ T cells in conditions such as chronic viral infection and in tumor immune evasion. The interaction of PD-1 with its ligand PD-L suppresses antitumor T cell function and indirectly stimulates Treg population. We investigated a hypothesis of whether examining PD-1 expression in peripheral T cells of patients with different lymphoma subtypes reflects tumor subtype or stage and compared results with healthy volunteers. Methods: Patients were assessed prior to their treatment or at the time of disease relapse or progression. We analyzed 5 patients with HL and 30 patients with NHL (T-cell n=6, diffuse large B-cell n=12, follicular lymphoma n=9, marginal zone lymphoma n=3). Twelve of the patients had relapsed or refractory diseases (B-NHL n=6, T-NHL n=2, HL n=4). Eleven patients (32%) had advanced (III/IV) disease stages. Data were compared with samples obtained from 12 healthy blood donors. Peripheral blood samples were stained with anti-CD3 FITC (Exbio), PD-1 (CD279) PE (BioLegend), anti-CD8 PerCP (Exbio), CD4 APC (Exbio), anti-CD25 FITC (BD), and anti-CD127 PE (BioLegend) using a lyse/no-wash protocol. Stained cells were acquired using the FACSCalibur cytometer (BD). Analysis of immunocompetent subpopulations was performed using the CellQuest Pro (BD) software. PD-1 (CD279) population was gated from CD3-positive T cells; minimal acquisition was designated as 10,000 CD3+ events. The percentage of PD-1+ cells within the live CD3+CD4+ and CD3+CD8+ populations was compared to isotype controls to establish baseline values. Absolute numbers were expressed as number of cells*10exp6 per liter. Population of Tregs was defined as CD4+/CD25int-hi / CD127low cells. Tregs were gated from CD4+ lymphocytes with minimal acquisition of 5,000 CD4+ cells. Results: Proportion of PD-1+/CD8+ of CD3+/CD8+ cells was significantly higher in patients with lymphoma than in healthy subjects: healthy volunteers (HV) 8.8%, B-NHL 16.0% (p=0.02), HL 21.8% (p<0.01), and T-NHL 30.8% (p<0.01). In absolute numbers of PD-1+/CD8+ cells, no significant difference was found when comparing healthy subjects and B-NHL: HV 0.23, B-NHL 0.56 (p=0.21), T-NHL 0.93 (p<0.01), and HL 1.51 (p<0.01). When analyzing the proportion of PD-1+/CD8+ cells according to disease phases, the highest numbers were found in patients with refractory/relapsed lymphoma as compared to patients with untreated disease and healthy subjects: HV 8.8%, untreated 14.6% (p=0.04), and relapsed 28.6% (p<0.01). Untreated patients had a significantly lower proportion of PD-1+/CD8+ cells than relapsed patients (p<0.01). Similar results were obtained with absolute numbers: HV 0.22, untreated 0.55 (p=0.03), and relapsed 1.24 (p=0.03). Untreated vs. relapsed patients p=0.05. Patients with limited disease stages had almost the same proportion of PD-1+/CD8+ lymphocytes compared to HV: HV 8.8%, limited stage 11% (p=0.21), and advanced stage 24.3% (p<0.01). In absolute numbers, HV had much less PD-1+/CD8+ cells in PB: HV 0.22, limited stage 0.49 (p<0.01), and advanced stage 0.97 (p<0.01). When analyzing the population of PD-1+/CD4+ cells, differences were only found in absolute numbers between HV (0.35) and HL (1.34; p<0.01), and between B-NHL (0.54) and HL (p=0.01). Regarding the population of Tregs, statistical differences were found between HV and B-NHL, HL or T-NHL in either relative or absolute numbers. On the other hand, there was a close correlation between absolute numbers of Tregs and PD-1+/CD4+ cells (p<0.01, correlation 0.73), and between Tregs and PD-1+/CD8+ cells (p<0.01, correlation 0.53). Conclusion: PD-1 expression in peripheral blood CD4+ and CD8+ cells is markedly different between lymphoma subtypes and compared with healthy subjects. The highest numbers of PD-1+/CD8+ are in patients with advanced lymphoma and at the time of disease relapse. This fact support the hypothesis that tumor clones actively switch effector CD8+ cells through the PD1L/PD-1 pathway into an immunotolerant state. PD-1 may be a potential marker of systemic immune dysregulation in lymphoma patients and further exploration of T cell subpopulations may define its role as a potential biomarker. Supported by grants: MSM 6198959205, LF-2012-007 and MZ ÈR IGA NT 11103. Disclosures: Prochazka: Roche: Travel grants Other.

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