Expression of Programmed Cell Death-L1 (PD-L1) Protein and Mismatch Repair Mutations in Orbital Tumours-a Pilot Study

2021 ◽  
pp. 112067212110662
Author(s):  
Mohammad A AlSemari ◽  
Diego Strianese ◽  
Leen Abu Safieh ◽  
Hailah Al Hussain ◽  
Malak Abedalthagafi ◽  
...  
Keyword(s):  
Cell Death ◽  
Pilot Study ◽  
Programmed Cell Death ◽  
Mismatch Repair ◽  
Tumour Progression ◽  
Pathogenic Mutation ◽  
Response To Treatment ◽  
Dna Mismatch ◽  
Formalin Fixed Paraffin Embedded ◽  
Orbital Tumours

Purpose Programmed cell death protein 1 (PD-1) and DNA mismatch repair (MMR) deficiency play an important role in tumour progression and response to treatment. Both markers have been studied in some ocular tumours but little is known about these markers in orbital tumours. This pilot study reports on PD-L1 expression and MMR mutations using next generation sequencing (NGS) in specific orbital tumours. Methods We reviewed surgical specimens from patients with rhabdomyosarcoma, adenoid cystic carcinoma (ACC), pleomorphic adenoma (PA) and biopsy negative tissue from orbital tumours used as a control. immunohistochemistry (IHC) was performed on Formalin fixed paraffin embedded tissue using a PD-L1 antibody. DNA was extracted for targeted gene panel NGS of the MMR genes PMS2, MLH1, MSH6 and MSH2. Results The study included 17 orbital specimens. Scattered membrane PD-L1 staining was noted in 3/6 rhabdomyosarcoma specimens without an accompanying lymphocytic infiltrate. PD-L1 immunostaining was absent in 3/3 ACC, and 5/6 PA specimens. PD-L1 immunostaining was not detected in 2/2 control specimens. 4/17 samples shared the same pathogenic mutation in the MLH1 gene, including 3/6 rhabdomyosarcoma and 1/3 ACC samples. 1/6 PA samples had a mutation in MSH6. Conclusions Our study demonstrated scattered, non-quantifiable or absent PD-L1 staining in a limited sample of orbital tumours suggesting that PD-1/PD-L1 inhibitor therapy may not be useful in treatment of malignant orbital tumours (rhabdomyosarcoma and ACC) when refractory to conventional therapy. Our pilot study suggest that PD-L1/MMR axis might not play a major role in the pathogenesis of primary orbital tumour.

scholarly journals Mismatch Repair Deficiency and Microsatellite Instability in Triple-Negative Breast Cancer: A Retrospective Study of 440 Patients

2021 ◽  
Vol 11 ◽  
Author(s):  
Xin-yu Ren ◽  
Yu Song ◽  
Jing Wang ◽  
Long-yun Chen ◽  
Jun-yi Pang ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cell Death ◽  
Programmed Cell Death ◽  
Microsatellite Instability ◽  
Mismatch Repair ◽  
Triple Negative Breast Cancer ◽  
Triple Negative ◽  
Low Frequency ◽  
Clinicopathological Parameters ◽  
Tissue Samples

PurposeTo investigate the status of mismatch repair (MMR) and microsatellite instability (MSI) in triple-negative breast cancer (TNBC) and to examine correlations between MMR/MSI status and clinicopathological parameters.MethodsWe retrospectively collected tissue samples from 440 patients with TNBC and constructed tissue microarrays. Protein expression of MLH1, MSH2, MSH6, and PMS2 was detected by immunohistochemistry (IHC). We also analyzed 195 patient samples using MSI polymerase chain reaction (PCR) testing. Correlations between MSI status and clinicopathological parameters and prognosis were analyzed.ResultsThe median age of the cohort was 49 years (range: 24–90 years) with a median follow-up period of 68 months (range: 1–170 months). All samples were positive for MLH1, MSH2, MSH6, and PMS2, except for one sample identified as MMR-deficient (dMMR) by IHC, with loss of MSH2 and intact MSH6 expression. MSI PCR revealed no case with high-frequency MSI (MSI-H), whereas 14 (7.2%) and 181 (92.8%) samples demonstrated low-frequency and absence of MSI events, respectively. The dMMR sample harbored low-frequency instability, as revealed by MSI PCR, and a possible EPCAM deletion in the tumor, as observed from next-generation sequencing. No correlations were detected between MMR or MSI status and clinicopathological parameters, programmed cell death 1 (PD-1)/programmed cell death ligand 1 (PD-L1) expression, or survival.ConclusionsThe incidence of dMMR/MSI-H is extremely low in TNBC, and rare discordant MSI PCR/MMR IHC results may be encountered. Moreover, MMR/MSI status may be of limited prognostic value. Further studies are warranted to explore other predictive immunotherapy biomarkers for TNBC.

scholarly journals Der Einsatz von Immuncheckpoint-Inhibitoren im onkologischen Alltag

2020 ◽  
Vol 79 (8) ◽  
pp. 809-817 ◽  
Author(s):  
Julian Schardt
Keyword(s):  
Cell Death ◽  
Programmed Cell Death ◽  
Mismatch Repair ◽  
T Lymphocyte ◽  
Cytotoxic T Lymphocyte ◽  
Programmed Cell Death 1

Zusammenfassung Hintergrund Die Einführung von Immuncheckpoint-Inhibitoren (ICI) hat die Behandlungskonzepte der Onkologie für eine Vielzahl von unterschiedlichen Krebsarten maßgeblich verändert. Dabei werden in der klinischen Routine v. a. humanisierte Antikörper gegen Immuncheckpoints wie „cytotoxic T‑lymphocyte associated protein 4“ (CTLA-4) oder „programmed cell death 1/programmed cell death ligand 1“ (PD1/PD-L1) eingesetzt. Fragestellung Übersicht zur Therapielandschaft mit Immuncheckpoint-Inhibitoren bei mehrheitlich soliden Tumoren in der Onkologie. Material und Methoden Darstellung und Diskussion aktueller Studienresultate, Einbezug aktueller Behandlungsempfehlungen und Zulassungsindikationen. Ergebnisse Sieben verschiedene Immuncheckpoint-Inhibitoren werden in der Onkologie therapeutisch eingesetzt: ein Anti-CTLA-4-Antikörper, 3 Anti-PD1-Antikörper und 3 Anti-PD-L1-Antiköper. FDA-Zulassung auf dem US-Markt für 17 verschiedene Tumorentitäten und einer agnostischen Indikation (Tumoren mit defizienter Mismatch-repair-Maschinerie/hohe Mikrosatelliteninstabilität). Langzeitremissionen sind in ca. zwei Drittel der Patienten mit Tumoransprechen möglich. Schlussfolgerungen Nutzen der Immuncheckpoint-Inhibitoren nur für einen Teil der behandelten Patienten. Primäre und sekundäre Resistenzmechanismen erst in Anfängen verstanden. Kombinationstherapien der Immuncheckpoint-Inhibitoren mit z. B. Chemotherapie, neuen Immuncheckpoint-Inhibitoren (z. B. Anti-LAG3-Antikörper) oder gezielten Therapien (z. B. CDK4/6, PARP-Inhibitoren) zur Verbesserung der Wirksamkeit werden in klinischen Studien untersucht. Verlässliche, prädiktive Marker sind dringend erforderlich.

Programmed cell death-1 rs2227981 polymorphism in patients with autoimmune skin blistering disorders: A pilot study

Meta Gene ◽  
2020 ◽  
Vol 26 ◽  
pp. 100793
Author(s):  
Valentina Faina ◽  
Alvise Sernicola ◽  
Irene Russo ◽  
Anna Michelotto ◽  
Vittorio Szathvary ◽  
...  
Keyword(s):  
Cell Death ◽  
Pilot Study ◽  
Programmed Cell Death ◽  
Programmed Cell Death 1

Differentiation and programmed cell death-related intermediate biomarkers for the development of non-small cell lung cancer: A pilot study

1998 ◽  
Vol 29 (9) ◽  
pp. 965-971 ◽  
Author(s):  
Haifan Zhang ◽  
Samuel A Yousem ◽  
Wilbur A Franklin ◽  
Elaine Elder ◽  
Rodney Landreneau ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Cell Death ◽  
Pilot Study ◽  
Programmed Cell Death ◽  
Small Cell Lung Cancer ◽  
Cell Lung Cancer ◽  
Small Cell ◽  
Small Cell Lung

scholarly journals PD-L1 quantification across tumor types using the reverse phase protein microarray: implications for precision medicine

2021 ◽  
Vol 9 (10) ◽  
pp. e002179
Author(s):  
Elisa Baldelli ◽  
K Alex Hodge ◽  
Guido Bellezza ◽  
Neil J Shah ◽  
Guido Gambara ◽  
...  
Keyword(s):  
Cell Death ◽  
Programmed Cell Death ◽  
High Throughput ◽  
Protein Microarray ◽  
Correlation Coefficients ◽  
Response To Treatment ◽  
Reverse Phase ◽  
Phase Protein ◽  
Reverse Phase Protein Microarray ◽  
Tumor Types

BackgroundAnti-programmed cell death protein 1 and programmed cell death ligand 1 (PD-L1) agents are broadly used in first-line and second-line treatment across different tumor types. While immunohistochemistry-based assays are routinely used to assess PD-L1 expression, their clinical utility remains controversial due to the partial predictive value and lack of standardized cut-offs across antibody clones. Using a high throughput immunoassay, the reverse phase protein microarray (RPPA), coupled with a fluorescence-based detection system, this study compared the performance of six anti-PD-L1 antibody clones on 666 tumor samples.MethodsPD-L1 expression was measured using five antibody clones (22C3, 28–8, CAL10, E1L3N and SP142) and the therapeutic antibody atezolizumab on 222 lung, 71 ovarian, 52 prostate and 267 breast cancers, and 54 metastatic lesions. To capture clinically relevant variables, our cohort included frozen and formalin-fixed paraffin-embedded samples, surgical specimens and core needle biopsies. Pure tumor epithelia were isolated using laser capture microdissection from 602 samples. Correlation coefficients were calculated to assess concordance between antibody clones. For two independent cohorts of patients with lung cancer treated with nivolumab, RPPA-based PD-L1 measurements were examined along with response to treatment.ResultsMedian-center PD-L1 dynamic ranged from 0.01 to 39.37 across antibody clones. Correlation coefficients between the six antibody clones were heterogeneous (range: −0.48 to 0.95) and below 0.50 in 61% of the comparisons. In nivolumab-treated patients, RPPA-based measurement identified a subgroup of tumors, where low PD-L1 expression equated to lack of response.ConclusionsContinuous RPPA-based measurements capture a broad dynamic range of PD-L1 expression in human specimens and heterogeneous concordance levels between antibody clones. This high throughput immunoassay can potentially identify subgroups of tumors in which low expression of PD-L1 equates to lack of response to treatment.

scholarly journals Immune System-Related Changes in Preclinical GL261 Glioblastoma under TMZ Treatment: Explaining MRSI-Based Nosological Imaging Findings with RT-PCR Analyses

Cancers ◽  
2021 ◽  
Vol 13 (11) ◽  
pp. 2663
Author(s):  
Pilar Calero-Pérez ◽  
Shuang Wu ◽  
Carles Arús ◽  
Ana Paula Candiota
Keyword(s):  
Cell Death ◽  
Immune System ◽  
Programmed Cell Death ◽  
Brain Tumours ◽  
Response To Treatment ◽  
Cell Type ◽  
Rt Pcr ◽  
Programmed Cell Death 1 ◽  
And Control ◽  
Future Work

Glioblastomas (GB) are brain tumours with poor prognosis even after aggressive therapy. Previous work suggests that magnetic resonance spectroscopic imaging (MRSI) could act as a biomarker of efficient immune system attack onto GB, presenting oscillatory changes. Glioma-associated microglia/macrophages (GAMs) constitute the most abundant non-tumour cell type within the GB and can be polarised into anti-tumour (M1) or pro-tumour (M2) phenotypes. One of the mechanisms to mediate immunosuppression in brain tumours is the interaction between programmed cell death-1 ligand 1 (PD-L1) and programmed cell death-1 receptor (PD-1). We evaluated the subpopulations of GAMs in responding and control GB tumours to correlate PD-L1 expression to GAM polarisation in order to explain/validate MRSI-detected findings. Mice were evaluated by MRI/MRSI to assess the extent of response to treatment and with qPCR for GAMs M1 and M2 polarisation analyses. M1/M2 ratios and PD-L1 expression were higher in treated compared to control tumours. Furthermore, PD-L1 expression was positively correlated with the M1/M2 ratio. The oscillatory change in the GAMs prevailing population could be one of the key causes for the differential MRSI-detected pattern, allowing this to act as immune system activity biomarker in future work.

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