812 PROGRAMMED CELL DEATH PROTEIN 1/PROGRAMMED DEATH LIGAND 1 AND HLA-CLASS I ARE POTENTIAL THERAPEUTIC TARGETS IN ESOPHAGEAL NEUROENDOCRINE CARCINOMA

2021 ◽  
Vol 34 (Supplement_1) ◽  
Author(s):  
Satoshi Ya Masthita ◽  
Hiroyuki Abe ◽  
Hiroharu Yamashita ◽  
Koichi Yagi ◽  
Yasuyuki Seto ◽  
...  
Keyword(s):  
Neuroendocrine Carcinoma ◽  
Therapeutic Targets ◽  
Tumor Infiltrating Lymphocytes ◽  
Hla Class I ◽  
Class I ◽  
Neuroendocrine Neoplasm ◽  
Programmed Death ◽  
Positive Score ◽  
Combined Positive Score ◽  
Infiltrating Lymphocytes

Abstract   Esophageal neuroendocrine carcinoma (NEC) is a rare and aggressive subtype with a poor prognosis. Pembrolizumab was recommended for the treatment of PD-L1 positive tumors in esophageal cancer and the combined positive score (CPS) was reported to be a better predictor of efficacy compared to the tumor proportion score (TPS). We investigated the expression profile of potential therapeutic targets (PD-L1, HLA class I, Mismatch repair (MMR) proteins) and tumor infiltrating lymphocytes (TILs) in esophageal NEC. Methods 15 NECs of the esophagus including mixed neuroendocrine-non-neuroendocrine neoplasm (MiNEN) with squamous cell carcinoma (SCC) component were investigated in the study. The expression of PD-L1 (quantitatively evaluated by CPS and TPS), HLA class I, and MMR protein expression were examined immunohistochemically. TIL abundance was examined semiquantitatively by observation of H&E slides. Results Nine (60%) showed a CPS ≥ 1, five (33%) showed a CPS ≥10, and five cases showed a TPS ≥1. Survival analysis showed a significantly longer overall survival in the CPS ≥1 group than in the CPS <1 group. Deficiency of MMR protein was not observed in any cases. HLA-Class I expression was retained in 10 (67%), and loss of HLA-Class I was significantly correlated with frequent lymph node metastasis, high TNM Stage, and low TIL. Three showed both PD-L1 CPS ≥ 10 and high TIL. Conclusion In esophageal NEC, PD-L1 positivity and preserved HLA-Class I expression were frequently observed, and PD-L1 CPS ≥ 1 was significantly associated with the better prognosis of esophageal NEC. Therefore, the PD-1/PD-L1 pathway and HLA-class I are thought to be potential therapeutic targets in esophageal neuroendocrine carcinoma.

HLA class-I-restricted and tumor-specific CTL in tumor-infiltrating lymphocytes of patients with gastric cancer

1997 ◽  
Vol 70 (6) ◽  
pp. 631-638 ◽  
Author(s):  
Tomoaki Hoshino ◽  
Naoko Seki ◽  
Megumi Kikuchi ◽  
Terukazu Kuramoto ◽  
Osamu Iwamoto ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Tumor Infiltrating Lymphocytes ◽  
Hla Class I ◽  
Class I ◽  
Infiltrating Lymphocytes

Association of DNA damage response and repair genes (DDR) mutations and microsatellite instability (MSI), PD-L1 expression, tumor mutational burden (TMB) in gastroesophageal cancers.

2019 ◽  
Vol 37 (4_suppl) ◽  
pp. 60-60 ◽  
Author(s):  
Michael Cerniglia ◽  
Joanne Xiu ◽  
Axel Grothey ◽  
Michael J. Pishvaian ◽  
Jimmy J. Hwang ◽  
...  
Keyword(s):  
Checkpoint Inhibitors ◽  
Gastroesophageal Junction ◽  
Tumor Infiltrating Lymphocytes ◽  
Fragment Analysis ◽  
Potential Biomarker ◽  
Tumor Mutational Burden ◽  
Positive Score ◽  
Combined Positive Score ◽  
Next Generation Sequencing Ngs ◽  
Infiltrating Lymphocytes

60 Background: DDR mutations are associated with higher neoantigen load and tumor infiltrating lymphocytes, and are a potential biomarker for immunotherapy. We investigated the association of DDR mutations in gastric (GC), esophageal (EC), and gastroesophageal junction (GEJ) cancers with MSI, PD-L1, and TMB, known predictors for immune checkpoint inhibitors. Methods: 20 DDR mutations were tested by Next-Generation Sequencing (NGS) with a 592-gene panel on a total of 1935 (709 EC; 831 GC; 355 GEJ) cancers. TMB was assessed by NGS, MSI by NGS or fragment analysis, and PD-L1 by IHC (22c3 for CPS or SP142). Results: GC had the highest DDR mutation rate compared to EC and GEJ (27% vs. 20%, p = 0.0005 and 17%, p = 0.0002, respectively). MSI-High (MSI-H) was significantly more common in the DDR mutated cohort (DDR-M) compared to non-mutated cancers (18% vs. 1%; p < 0.0001). TMB-High (≥ 10 mutations/megabase [mt/MB]) was higher in DDR-M (35% vs. 21%; p < 0.0001); in DDR-M cohort, GC had the highest TMB compared to DDR-M EC and GEJ (mean: 13.8 vs. 9.4 vs. 10 mt/MB, respectively; p < 0.0001). DDR mutations were more frequent in the PD-L1 combined positive score (CPS) ≥ 50 group than CPS 0 (42.9% vs. 24%; p = 0.037) and CPS 1-9 (42.9% vs. 20.6%; p = 0.005). ARID1A, ATRX, BRCA2, and PTEN were the most prevalent DDR mutations in MSI-H (87%, 31%, 25%, 24%, respectively); ARID1A, ATRX, BRCA2, and PTEN in TMB-High (47%, 7.7%, 6.7%, 6.8%) and ARID1A, BRCA2, RAD50, and WRN in PD-L1 high (CPS ≥ 10) (48.5% vs. 5.2% vs. 2.5% vs. 3.4%). Conclusions: MSI-H, TMB-high and high PD-L1 expression were significantly more prevalent in the DDR-M cohort compared to non-DDR-mutated cancers, most pronounced in GC. Alterations in ARID1A, ATRX, BRCA2, and PTEN were correlated with MSI-H and TMB-high while ARID1A, BRCA2, RAD50, and WRN were correlated with increased PD-L1 expression. Our findings may help identify patients for tailored immunotherapy approaches in future clinical trials.

scholarly journals Immune checkpoint markers in gastroenteropancreatic neuroendocrine neoplasia

2019 ◽  
Vol 26 (3) ◽  
pp. 293-301 ◽  
Author(s):  
Florian Bösch ◽  
Katharina Brüwer ◽  
Annelore Altendorf-Hofmann ◽  
Christoph J Auernhammer ◽  
Christine Spitzweg ◽  
...  
Keyword(s):  
Patient Survival ◽  
Tumor Infiltrating Lymphocytes ◽  
Cell Surface Receptor ◽  
Clinicopathological Parameters ◽  
Term Survival ◽  
Programmed Death ◽  
Promising Therapeutic Approach ◽  
Surface Receptor ◽  
Programmed Death 1 ◽  
Infiltrating Lymphocytes

Cancer immunotherapy has evolved major breakthroughs in the last years. The cell-surface receptor programmed death-1 (PD-1) and its ligand, programmed death ligand-1 (PD-L1), have been detected in various cancer types. However, the analysis on gastroenteropancreatic neoplasia (GEP-NENs) is limited. Therefore, the aim of this study was to characterize GEP-NENs with regard to PD-1/PD-L1 pathway and tumor-infiltrating lymphocytes (TILs). On protein level, we examined TILs, PD-1 and PD-L1 expression in tumor tissue of 244 GEP-NENs using immunohistochemistry. Expression levels were correlated with clinicopathological parameters including long-term survival in an observational study. In total, 244 patients could be included. Most of the patients had a NEN of the small intestine (52.5%) or the pancreas (29.5%). All tumors could be graded by their morphology and Ki67 index, with 57.8% G1, 34% G2 and 8.2% G3 tumors. High TILs (19.6%) and high PD-1 (16.1%) expression showed a significant correlation with shorter patient survival (P < 0.05) and with a higher grading. Furthermore, expression of PD-L1 (8.7%) showed a trend to shorter patient survival. High TILs and PD-1 expression are significantly associated with shorter patient survival and higher grading in GEP-NENs. PD-L1 expression showed a trend to shorter patient survival. Immunotherapy might be a promising therapeutic approach in GEP-NENs especially in tumors with high TILs.

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