Significance of Detection of the HER2 Gene and PD-1/PD-L1 in Gastric Cancer

Yun, Tian; Wang, Sunan; Jiang, Bo; Wang, Changsong; Meng, Nian-Long; Yuan, Xutao; Wang, Yangkun

doi:10.1155/2020/8678945

Cited by 14 publications

(9 citation statements)

References 20 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: 85%

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: 85%

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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“…In addition, trastuzumab induces anti-tumor effects by promoting the activation of natural killer cells in an antibodydependent manner [28] . Trastuzumab is approved for clinical use in patients with HER2-positive GAC [29] . However, the effectiveness of combination therapy comprising immune checkpoint inhibitors and anti-HER2 drugs in HER2 overexpression GAC needs to be studied in the future [9][10][11] .…”

Section: Article In Pressmentioning

confidence: 99%

PD-L1 and HER2 expression in gastric adenocarcinoma and their prognostic significance

Lian

Zhang

et al. 2022

Digestive and Liver Disease

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Background: The upregulation of programmed death-ligand 1 (PD-L1) and epidermal growth factor receptor 2 (HER2) may play a role in gastric adenocarcinoma (GAC). Aim: To study PD-L1 and HER-2 expression and prognosis in GAC. Methods: PD-L1 and HER2 expression was determined in tumor tissues of 75 patients with GAC. The correlations between PD-L1, HER2 expression, and clinicopathological factors were analyzed. Results: The positive expression rate for PD-L1 was 57.3% (43/75) and the HER2 over-expression rate was 17.3% (13/75). PD-L1 expression negatively correlated with the grade of GAC differentiation (r = -0.26, P < 0.05). Approximately 85% of HER2-positive GACs were found to be PD-L1-positive and PD-L1 expression positively correlated with HER2 overexpression. The TNM stage and combined HER2 and PD-L1 expression were independent prognostic factors affecting the survival of patients with GAC. The median overall survival and recurrence-free survival of groups I (HER2 overexpression and PD-L1 positive), II (HER2 overexpression and PD-L1 negative), III (No HER2 overexpression and PD-L1 positive) and IV (No HER2 overexpression and PD-L1 negative) were (47 (17-77), 15 (0-44), 81 (62-101), and 78 (60-98) months, respectively. Conclusion: PD-L1 expression is upregulated in more than half of patients with GAC. Anti-PD-L1 treatment combined with anti-HER2 therapy may benefit patients with locally advanced GAC with HER2 overexpression.

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“…More than 75% of the tumor cell nuclei had a hybridization signal, and at least 30 nonoverlapping cancer cells with complete boundaries were counted using 100× objective lens. The ratios of HER2/CEP17 were calculated as follows: the HER2/CEP17 ratio ≥2.0 and average HER2 copies/cells ≥4.0 were defined as HER2 gene positive amplification, while the HER2/CEP17 ratio <2.0 and average HER2 copies/cells<4.0 were defined as HER2 gene negative amplification, as described in [ 45 ].…”

Section: Methodsmentioning

confidence: 99%

The Influence of Heavy Metals on Gastric Tumorigenesis

Wang

Miao

et al. 2022

Journal of Oncology

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Objectives. This study aimed to observe the relationship among heavy metals concentration, microsatellite instability (MSI), and human epidermal growth factor receptor type 2 (HER2) gene amplification in gastric cancer (GC) patients. Methods. The concentrations of 18 heavy metals in the plasma of GC patients and healthy controls were measured by inductive coupled plasma emission spectrometry (ICP-MS). MSI detection was conducted by detecting 5 microsatellite repeat markers by PCR analysis. HER2 gene amplification was detected by fluorescence in situ hybridization (FISH). The relationship among heavy metal elements, tumor biomarkers, HER2 amplification, and MSI status was analyzed by Pearson correlation analysis. Results. A total of 105 GC patients and 62 healthy controls were recruited in this study. The concentration of arsenic (As), chromium (Cr), cuprum (Cu), mercury (Hg), manganese (Mn), lead (Pb), stibium (Sb), selenium (Se), stannum (Sn), strontium (Sr), thallium (Tl), vanadium (V), and zinc (Zn) were significantly different between GC patients and controls. Among 105 GC patients, including 87 microsatellite-stable (MSS) samples and 18 MSI samples, the concentration of Ga is significantly higher in the MSI group than that in the MSS group. Meanwhile, in 97 GC patients having detected HER2 gene amplification, 69 of 97 had negative HER2 gene amplification and the rest 28 GC patients had positive HER2 gene amplification. The concentration of Hg, Sn, and Tl is noticeably higher in the HER2 positive group than in the HER2 negative group. Only Sb was positively correlated with MSI, but none of these heavy metals was correlated with HER2 gene amplification. Conclusions. The results indicated that Sb has significant positive correlation with the MSI status, which suggests that Sb may cause MSI in GC. However, further research studies are required to elucidate the mechanisms in the near feature.

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Significance of Detection of the HER2 Gene and PD-1/PD-L1 in Gastric Cancer

Cited by 14 publications

References 20 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

PD-L1 and HER2 expression in gastric adenocarcinoma and their prognostic significance

The Influence of Heavy Metals on Gastric Tumorigenesis

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