PD-L1 and HER2 Expression in Gastroesophageal Cancer: a Matched Case Control Study

Beer, Andrea; Taghizadeh, Hossein; Schiefer, Ana‐Iris; Puhr, Hannah Christina; Karner, Alexander; Jomrich, Gerd; Schoppmann, Sebastian F.; Kain, Renate; Preusser, Matthias; Ilhan-Mutlu, Aysegül

doi:10.1007/s12253-020-00814-2

Cited by 18 publications

(14 citation statements)

References 36 publications

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“…Using patient gastric cancer tissue for DSP analysis and organoid cultures derived from HER2-positive and -negative gastric cancer patients, our present study documents that HER2 and PD-L1 were jointly detected in gastric cancer. Our data is strongly supported by published studies that have performed extensive immunohistochemical and fluorescence in situ hybridization to show that HER2 and PD-L1 are not only co-expressed but related to the gastric cancer stage and lymph node metastasis [ 36 , 37 , 38 , 39 , 40 , 41 ]. We used autologous gastric cancer patient-derived organoid/immune cell co-culture models [ 30 ] to identify the mechanisms by which HER2 regulates the expression of PD-L1 in gastric cancer.…”

Section: Discussionsupporting

confidence: 86%

Disruption of Her2-Induced PD-L1 Inhibits Tumor Cell Immune Evasion in Patient-Derived Gastric Cancer Organoids

Chakrabarti

Koh

Steele

et al. 2021

Cancers

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(1) Background: The expression of programmed death-ligand 1 (PD-L1), which interacts with programmed cell death protein 1 (PD-1) on cytotoxic T lymphocytes (CTLs), enables tumors to escape immunosurveillance. The PD-1/PD-L1 interaction results in the inhibition of CTL proliferation, and effector function, thus promoting tumor cell evasion from immunosurveillance and cancer persistence. Despite 40% of gastric cancer patients exhibiting PD-L1 expression, only a small subset of patients responds to immunotherapy. Human epidermal growth factor receptor2 (HER2) is one of the critical regulators of several solid tumors, including metastatic gastric cancer. Although half of PD-L1-positive gastric tumors co-express HER2, crosstalk between HER2 and PD-1/PD-L1 in gastric cancer remains undetermined. (2) Methods: Human gastric cancer organoids (huTGOs) were generated from biopsied or resected tissues and co-cultured with CTLs and myeloid-derived suppressor cells (MDSCs). Digital Spatial Profiling (DSP) was performed on FFPE tissue microarrays of numerous gastric cancer patients to examine the protein expression of immune markers. (3) Results: Knockdown of HER2 in PD-L1/HER2-positive huTGOs led to a concomitant decrease in PD-L1 expression. Similarly, in huTGOs/immune cell co-cultures, PD-L1 expression decreased in huTGOs and was correlated with an increase in CTL proliferation which enhanced huTGO death. Treatment with Nivolumab exhibited similar effects. However, a combinatorial treatment with Mubritinib and Nivolumab was unable to inhibit HER2 expression in co-cultures containing MDSCs. (4) Conclusions: Our study suggested that co-expression of HER2 and PD-L1 may contribute to tumor cell immune evasion. In addition, autologous organoid/immune cell co-cultures can be exploited to effectively screen responses to a combination of anti-HER2 and immunotherapy to tailor treatment for gastric cancer patients.

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Section: Discussionsupporting

confidence: 86%

Disruption of Her2-Induced PD-L1 Inhibits Tumor Cell Immune Evasion in Patient-Derived Gastric Cancer Organoids

Chakrabarti

Koh

Steele

et al. 2021

Cancers

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“…Although some studies focused on the expression of PD-L1 and HER-2 in gastric cancer, the results of these studies are not consistent. Some researchers have found that expression of PD-L1, a potential biomarker for the immunotherapy response, was observed in HER-2 positive and negative patients to a similar extent, and its presence was not influenced by the HER-2 status ( 28 ). However, it has also been studied that the PD-L1 expression in GC is significantly correlated with HER2-negative status ( 29 ).…”

Section: Introductionmentioning

confidence: 99%

Expression of Human Epidermal Growth Factor Receptor-2 Status and Programmed Cell Death Protein-1 Ligand Is Associated With Prognosis in Gastric Cancer

Zhang²,

Sun

et al. 2021

Front. Oncol.

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BackgroundPD-L1 and HER-2 are routine biomarkers for gastric cancer (GC). However, little research has been done to investigate the correlation among PD-L1, HER-2, immune microenvironment, and clinical features in GC.MethodsBetween January 2013 and May 2020, a total of 120 GC patients treated with chemotherapy were admitted to Henan Tumor Hospital. We retrospectively identified PD-L1, HER-2 level before chemotherapy and abstracted clinicopathologic features and treatment outcomes. Univariate and multivariate survival analyses were performed to assess the relationship between PD-L1/HER-2 levels and progression-free survival (PFS). The mRNA and tumor microenvironment of 343 patients with GC from The Cancer Genome Atlas (TCGA) were used to explore the underlying mechanism.ResultsWe retrospectively analyzed 120 patients with gastric cancer, including 17 patients with HER-2 positive and 103 patients with HER-2 negative GC. The results showed that the expression of PD-L1 was closely correlated with HER-2 (P = 0.015). Patients with PD-L1/HER-2 positive obtained lower PFS compared to PD-L1/HER-2 negative (mPFS: 6.4 vs. 11.1 months, P = 0.014, mPFS: 5.3 vs. 11.1 months, P = 0.002, respectively), and the PD-L1 negative and HER-2 negative had the best PFS than other groups (P = 0.0008). In a multivariate model, PD-L1 status, HER-2 status, tumor location, and tumor differentiation remained independent prognostic indicators for PFS (P < 0.05). The results of database further analysis showed that the proportion of PD-L1+/CD8A+ in HER-2 negative patients was higher than that in HER-2 positive patients (37.6 vs 20.3%), while PD-L1−/CD8A− was significantly higher in HER-2 positive patients than HER-2 negative patients (57.8 vs. 28.8%). In addition, it showed that not only CD4+T cells, macrophages, and CD8+T cells, but also the associated inflammatory pathways such as IFN-γ/STAT1 were associated with HER-2.ConclusionHER-2 status could predict the efficacy of immune checkpoint inhibitors, and HER-2 status combined with PD-L1 level could predict the prognosis of GC patients.

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“… 3 A comprehensive study by “The Cancer Genome Atlas” (TCGA) consortium reported 4 molecular subtypes of GC: chromosomal instability (CIN), microsatellite instability-high (MSI), genomically stable, and Epstein-Barr virus (EBV) molecular subtypes. 5 However, the clinical significance of these subtypes has not been clearly clarified. The Asian Cancer Research Group (ACRG) reported 4 molecular subtypes of GC including microsatellite-stable (MSS)/TP53-, MSS/TP53+, MSI, and epithelial-to-mesenchymal transition (EMT) subtypes.…”

Section: Discussionmentioning

confidence: 99%

“…Although the subclassification by molecular testing might increase the complexity of classification, identifying subtypes of gastric cancer based on molecular and genetic features is necessary to select targeted treatment to increase survival rate in the patients with gastric cancer. 5 Based on previous studies, multiple molecular classification has been introduced. However, there is a need for comprehensive molecular classification that correlates with histological features, clinical outcome, and prognosis of the gastric cancer.…”

Section: Introductionmentioning

confidence: 99%

Molecular Classification of Gastric Cancer With Emphasis on PDL-1 Expression: The First Report From Iran

Amirmoezi

Geramizadeh

2022

Clin Med�Insights�Pathol

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Background: Gastric cancer is one of the lethal cancers and there is no effective treatment for these patients and still, 5-year survival rate is about 25% to 30%. Finding reliable biomarkers for early-stage diagnosis, targeted therapy, and survival prediction is a priority in this cancer. Objectives: In this study we were trying to know about the molecular classification of gastric cancers in a group of patients from the South of Iran. Patients and Methods: In a cross sectional study, 50 specimens of gastric cancer were selected that have enough tissue to be stained by immunohistochemistry (IHC). IHC was performed for Her-2, mismatch repair genes (MLH-1, MSH-2, MSH-6, and PMS-2), and PDL-1. Frequency of positive makers was compared with survival and outcome. Results and Conclusion: In our study, deficient MMR (dMMR) was detected in 4 patients (8.0%). PD-L1 expression in tumor cells (TC) was observed in 1 of 4 cases (25%) with PMS2 loss. However, PD-L1 in TCs and TILs (tumor infiltrating lymphocytes) was negative in 1 case with MLH1 loss and in 3 of 4 cases with PMS2 loss, which was not statistically significant. All of our 50 cases were positive for MSH2 and MSH6, 24% of which showed TCs with PDL-1 expression and 32% of them in TIL. HER2 was positive in 2 (2/50, 4.0%) cases, among which all of the cases were positive for PD-L1 expression in TCs and TILs, respectively. However, in HER2-negative group, 26.2% (11/42) and 28.6% (12/42) of tumors were positive for PD-L1 in TCs and TILs, respectively. The expression rate of PD-L1 in HER2 negative TCs was significantly higher than that in HER2 positive TCs ( P = .033). Immunohistochemistry for Her-2 was equivocal in 6 cases (12.0%) none of which expressed PD-L1 in tumor cells. In our study minimum and maximum survival times from detection of gastric cancer were 1 and 87 months, respectively. The mean ± SD and median ± SD of overall survival time were 30.69 ± 4.88 and 18 ± 1.45 months, respectively. One and 3-year survival rates of 40% and 24%, respectively. PD-L1 expression was not associated with survival, but its expression was associated with intestinal type Lauren classification and negative HER-2. PD-L1 positivity in tumor cells or tumor infiltrating lymphocytes was not an independent prognostic factor in gastric cancer.

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PD-L1 and HER2 Expression in Gastroesophageal Cancer: a Matched Case Control Study

Cited by 18 publications

References 36 publications

Disruption of Her2-Induced PD-L1 Inhibits Tumor Cell Immune Evasion in Patient-Derived Gastric Cancer Organoids

Disruption of Her2-Induced PD-L1 Inhibits Tumor Cell Immune Evasion in Patient-Derived Gastric Cancer Organoids

Expression of Human Epidermal Growth Factor Receptor-2 Status and Programmed Cell Death Protein-1 Ligand Is Associated With Prognosis in Gastric Cancer

Molecular Classification of Gastric Cancer With Emphasis on PDL-1 Expression: The First Report From Iran

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