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

Chakrabarti, Jayati; Koh, Vivien; Steele, Nina G.; Ito, Yoshiaki; Merchant, Juanita L.; Wang, Jiang; Helmrath, Michael A.; Ahmad, Syed A.; So, Jimmy Bok Yan; Yong, Wei Peng; Zavros, Yana

doi:10.3390/cancers13246158

Cited by 19 publications

(35 citation statements)

References 60 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…After establishing tumor models in mice by orthotopic transplantation, these cancer organoids can predict the efficacy of PD-1/PD-L1 blockade as well as other treatment regimens [ 258 – 261 ]. These studies used organoids to investigate PD-1/PD-L1 interaction in various aspects, including testing the anticancer efficacy of PD-1/PD-L1 inhibitors [ 261 – 263 ], analyzing the regulation mechanism of PD-L1 expression [ 258 , 259 ], finding strategies to enhance the therapeutic effect of PD-1/PD-L1 blockade [ 260 , 264 – 268 ], finding new immune checkpoints [ 269 ]. Through these studies, we can see that cancer organoids can be used to simulate the immune microenvironment in cancer patients, providing an effective tool for improving the efficacy of PD-1/PD-L1 blockade.…”

Section: Preclinical Models Used In Research About Pd-1/pd-l1 Blockadementioning

confidence: 99%

Improvement of the anticancer efficacy of PD-1/PD-L1 blockade via combination therapy and PD-L1 regulation

et al. 2022

View full text Add to dashboard Cite

Immune checkpoint molecules are promising anticancer targets, among which therapeutic antibodies targeting the PD-1/PD-L1 pathway have been widely applied to cancer treatment in clinical practice and have great potential. However, this treatment is greatly limited by its low response rates in certain cancers, lack of known biomarkers, immune-related toxicity, innate and acquired drug resistance, etc. Overcoming these limitations would significantly expand the anticancer applications of PD-1/PD-L1 blockade and improve the response rate and survival time of cancer patients. In the present review, we first illustrate the biological mechanisms of the PD-1/PD-L1 immune checkpoints and their role in the healthy immune system as well as in the tumor microenvironment (TME). The PD-1/PD-L1 pathway inhibits the anticancer effect of T cells in the TME, which in turn regulates the expression levels of PD-1 and PD-L1 through multiple mechanisms. Several strategies have been proposed to solve the limitations of anti-PD-1/PD-L1 treatment, including combination therapy with other standard treatments, such as chemotherapy, radiotherapy, targeted therapy, anti-angiogenic therapy, other immunotherapies and even diet control. Downregulation of PD-L1 expression in the TME via pharmacological or gene regulation methods improves the efficacy of anti-PD-1/PD-L1 treatment. Surprisingly, recent preclinical studies have shown that upregulation of PD-L1 in the TME also improves the response and efficacy of immune checkpoint blockade. Immunotherapy is a promising anticancer strategy that provides novel insight into clinical applications. This review aims to guide the development of more effective and less toxic anti-PD-1/PD-L1 immunotherapies.

show abstract

Section: Preclinical Models Used In Research About Pd-1/pd-l1 Blockadementioning

confidence: 99%

Improvement of the anticancer efficacy of PD-1/PD-L1 blockade via combination therapy and PD-L1 regulation

et al. 2022

View full text Add to dashboard Cite

show abstract

“…Distinct from our case, previous studies have suggested that HER-2 -positive status is related to the improvement of prognosis ( 18 , 53 ). Furthermore, some studies have proposed that the co-expression of HER-2 and PD-L1 may contribute to the immune escape of GC, meaning that HER-2 -negative status creates favorable conditions for effective immunotherapy ( 12 ). Compared with EGFR wild-type patients, patients with advanced non-small cell lung cancer with EGFR mutation show poor efficacy of PD-1/PD-L1 inhibitor treatment ( 54 ).…”

Section: Discussionmentioning

confidence: 99%

Case Report: Complete Remission of a Patient With Metastatic Gastric Cancer Treated With Nivolumab Combined With Chemotherapy After Palliative Surgery

et al. 2022

View full text Add to dashboard Cite

Metastatic advanced gastric cancer, for which treatment strategies are extremely limited, has a poor prognosis. Complete remission is rare. Patients usually lose the opportunity of therapeutic surgery because the lesions cannot be completely removed, although it can greatly prolong their survival time. Palliative surgery usually suggests bad outcomes. In recent years, the immune checkpoint inhibitor (ICI) nivolumab has shown significant efficacy in the treatment of advanced gastric cancer. However, its applicable conditions and optimal withdrawal time remain controversial owing to its low response rate and high incidence of immune-related adverse events. Herein, we introduce a 66-year-old male patient with advanced gastric cancer with multiple liver metastases who underwent laparoscopic total gastrectomy for acute gastric bleeding. The patient received eight cycles of S-1 plus oxaliplatin (SOX) and switched to eight cycles of SOX plus nivolumab combined regimen in a stable state, later achieving complete remission. There was no recurrence for 32 months after the surgery. This is the first reported case of gastric cancer with multiple liver metastases with long-term complete remission with nivolumab treatment after palliative surgery. The potential mechanism of complete remission was discussed through clinical, genomic, and immune characteristics. The patient had a history of psoriasis and was positive for programmed death ligand 1 (PD-L1), and the interaction of TP53 mutation and HER-2 (-) gene may be associated with complete remission.

show abstract

“…As pembrolizumab plus trastuzumab improved the response rate, combination therapy might be rational. In a previous study using patient-derived GC organoids, PD-L1 expression decreased in knockdown of HER2 resulting in the inhibition of the AKT-mTOR pathway in PD-L1/HER2-positive GC cells and was correlated with an increase in cytotoxic T lymphocyte proliferation [ 44 ]. These results suggest that the co-expression of HER2 and PD-L1 may contribute to tumor cell immune evasion.…”

Section: Immune Checkpoint Inhibitors For Gastric Cancermentioning

confidence: 99%

Gastric cancer and genomics: review of literature

2022

View full text Add to dashboard Cite

Gastric cancer (GC) is a major health concern in many countries. GC is a heterogeneous disease stratified by histopathological differences. However, these variations are not used to determine GC management. Next-generation sequencing (NGS) technologies have become widely used, and cancer genomic analysis has recently revealed the relationships between various malignant tumors and genomic information. In 2014, studies using whole-exome sequencing (WES) and whole-genome sequencing (WGS) for GC revealed the entire structure of GC genomics. Genomics with NGS has been used to identify new therapeutic targets for GC. Moreover, personalized medicine to provide specific therapy for targets based on multiplex gene panel testing of tumor tissues has become of clinical use. Recently, immune checkpoint inhibitors (ICIs) have been used for GC treatment; however, their response rates are limited. To predict the anti-tumor effects of ICIs for GC and to select patients suitable for ICI treatment, genomics also provides informative data not only of tumors but also of tumor microenvironments, such as tumor-infiltrating lymphocytes. In therapeutic strategies for unresectable or recurrent malignant tumors, the target is not only the primary lesion but also metastatic lesions, and metastatic lesions are often resistant to chemotherapy. Unlike colorectal carcinoma, there is a heterogeneous status of genetic variants between the primary and metastatic lesions in GC. Liquid biopsy analysis is also helpful for predicting the genomic status of both primary and metastatic lesions. Genomics has become an indispensable tool for GC treatment and is expected to be further developed in the future.

show abstract

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

Cited by 19 publications

References 60 publications

Improvement of the anticancer efficacy of PD-1/PD-L1 blockade via combination therapy and PD-L1 regulation

Improvement of the anticancer efficacy of PD-1/PD-L1 blockade via combination therapy and PD-L1 regulation

Case Report: Complete Remission of a Patient With Metastatic Gastric Cancer Treated With Nivolumab Combined With Chemotherapy After Palliative Surgery

Gastric cancer and genomics: review of literature

Contact Info

Product

Resources

About