Immune evasion mechanisms and therapeutic strategies in gastric cancer

Release of immunoreactive negative regulatory factors such as immune checkpoint limits antitumor responses. PD-L1 as a significant immunosuppressive factor has been involved in resistance to therapies such as chemotherapy and target therapy in various cancers. Via interacting with PD-1, PD-L1 can regulate other factors or lead to immune evasion of cancer cells. Besides, immune checkpoint blockade targeting PD-1/PD-L1 has promising therapeutic efficacy in the different tumors, but a significant percentage of patients cannot benefit from this therapy due to primary and acquired resistance during treatment. In this review, we described the utility of PD-L1 expression levels for predicting poor prognosis in some tumors and present evidence for a role of PD-L1 in resistance to therapies through PD-1/PD-L1 pathway and other correlating signaling pathways. Afterwards, we elaborate the key mechanisms underlying resistance to PD-1/PD-L1 blockade in cancer immunotherapy. Furthermore, promising combination of therapeutic strategies for patients resistant to PD-1/PD-L1 blockade therapy or other therapies associated with PD-L1 expression was also summarized.

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Overexpression of DAPK1-mediated inhibition of IKKβ/CSN5/PD-L1 axis enhances natural killer cell killing ability and inhibits tumor immune evasion in gastric cancer

Cellular Immunology ◽

10.1016/j.cellimm.2021.104469 ◽

2021 ◽

pp. 104469

Author(s):

Zhiyuan Guo ◽

Cheng Zhou ◽

Linsen Zhou ◽

Zhiqiang Wang ◽

Xinguo Zhu ◽

...

Keyword(s):

Gastric Cancer ◽

Natural Killer Cell ◽

Natural Killer ◽

Immune Evasion ◽

Killer Cell ◽

Cell Killing ◽

Tumor Immune Evasion

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Multicellular gastric cancer spheroids represent a valid model for pre-clinical testing of new therapeutic strategies

European Journal of Cancer ◽

10.1016/s0959-8049(01)80347-6 ◽

2001 ◽

Vol 37 ◽

pp. S11

Author(s):

B. Mayer ◽

G. Klement ◽

M. Kaneko ◽

S. Jothy ◽

R.S. Kerbel

Keyword(s):

Gastric Cancer ◽

Therapeutic Strategies ◽

Clinical Testing ◽

Valid Model ◽

Cancer Spheroids

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Mitoxantrone dihydrochloride, an FDA approved drug, binds with SARS-CoV-2 NSP1 C-terminal

10.1101/2021.09.14.460211 ◽

2021 ◽

Author(s):

Prateek Kumar ◽

Taniya Bhardwaj ◽

Rajanish Giri

Keyword(s):

Structural Dynamics ◽

Immune Evasion ◽

Drug Target ◽

Mrna Translation ◽

Small Subunit ◽

Therapeutic Strategies ◽

Spectroscopic Technique ◽

Terminal Region ◽

Binding Assays ◽

Computational Simulations

One of the major virulence factors of SARS-CoV-2, NSP1, is a vital drug target due to its role in host immune evasion through multiple pathways. NSP1 protein is associated with inhibiting host mRNA translation by binding to the small subunit of ribosome through its C-terminal region. Previously, we have shown the structural dynamics of NSP1 C-terminal region (NSP1-CTR) in different physiological environments. So, it would be very interesting to investigate the druggable compounds that could bind with NSP1-CTR. Here, in this article, we have performed the different spectroscopic technique-based binding assays of an anticancer drug Mitoxantrone dihydrochloride (MTX) against the NSP1-CTR. We have also performed molecular docking followed by computational simulations with two different forcefields up to one microsecond. Overall, our results have suggested good binding between NSP1-CTR and MTX and may have implications in developing therapeutic strategies targeting NSP1 protein of SARS-CoV-2.

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

Cancers ◽

10.3390/cancers13246158 ◽

2021 ◽

Vol 13 (24) ◽

pp. 6158

Author(s):

Jayati Chakrabarti ◽

Vivien Koh ◽

Nina Steele ◽

Jennifer Hawkins ◽

Yoshiaki Ito ◽

...

Keyword(s):

Gastric Cancer ◽

Tumor Cell ◽

Cancer Patients ◽

Immune Evasion ◽

Immune Cell ◽

Suppressor Cells ◽

Small Subset ◽

Human Gastric Cancer ◽

Her2 Positive ◽

Gastric Cancer Patients

(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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Real-world fusion landscape in advanced Chinese gastric cancer using next generation sequencing: A multicenter study.

Journal of Clinical Oncology ◽

10.1200/jco.2019.37.4_suppl.51 ◽

2019 ◽

Vol 37 (4_suppl) ◽

pp. 51-51

Author(s):

Rongbo Lin ◽

Shen Zhao ◽

Lisheng Cai ◽

Shaoqin Chen ◽

Jinhuo Lai ◽

...

Keyword(s):

Gastric Cancer ◽

Next Generation Sequencing ◽

Multicenter Study ◽

Index Patient ◽

Therapeutic Strategies ◽

Next Generation ◽

Entire Cohort ◽

Next Generation Sequencing Ngs ◽

Disease Cell ◽

Generation Sequencing

51 Background: Gastric cancer (GC) is a highly heterogeneous disease. Cell-free DNA (cfDNA) has been a research hotspot in molecular tumor profiling. In advanced GC patients, malignant pleural effusion (MPE) and ascites provide a wealth of tumor cells that can be investigated. The aim of this study is to investigate fusion landscape in advanced GC. Methods: A multicenter study in China was initiated from Aug. 2016, and GC patients have been enrolled as of Aug. 2018. To determine the fusion frequency in GC, we analyzed data from 371clinical GC cases, each of which had results from next-generation sequencing (NGS)-based 381 genes panel assay, analogous to the index patient. Results: Of this entire cohort, 61 patients (16.44%) were identified with fusions, including TMEM45B-FGF3 (3), AXIN1-SMPD3 (3), B3GNTL1-ERBB2 (2), ERBB2-LAMA3 (2), ERBB2-ACLY (2), TRIM24-BRAF (2), ARHGEF1-CD79A (2), FGFR4-UIMC1 (2), MSH2-TTC7A (2), SMARCA4-LDLR (2), GON4L-RIT1 (2), AKT1-CPSF2 (2), GATA6-COLEC12 (2), RICTOR-EFNA5 (2), KAT6A-PLAT (2), ROCK1-CCDC178 (2), HBS1L-MYB (2), SLC30A2-ARID1A (2), MSI2-BIRC5 (2), NOTCH3-UCA1 (2), PIK3C2B-KISS1 (2), RICTOR-OSMR (2), FGFR2-MIR5694 (2), FGFR2-FGFR1 (2), MAN2A2-BLM (2), EGFR-MED15 (1), EML4-ALK(1), GOPC-ROS1 (1), FXR2-TP53 (1), NF1-PSMD11 (1), IRS2-PRKCI (1), FGFR2-KIAA1217(1), FGFR2-TACC2 (1), FGFR3-TACC3 (1). ERBB2, BRAF, EGFR, ALK and ROS1 fusionswere seen in 18.03% (11/61) of advanced Chinese gastric cancer fusion landscape patients. Conclusions: Advanced Chinese gastric cancer fusion landscape is rich, ERBB2, BRAF, EGFR, ALK and ROS1 fusions are rare but potentially druggable in TKIs. Detection of ERBB2, BRAF, EGFR, ALK and ROS1 fusions should be part of comprehensive profiling panels to determine TKIs and direct appropriate combination therapeutic strategies.

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Diagnostic and therapeutic strategies for gastric cancer in the era of precision medicine

Annals of Research Hospitals ◽

10.21037/arh.2017.04.08 ◽

2017 ◽

Vol 1 ◽

pp. 1-1

Author(s):

Kecheng Zhang ◽

Xiaohui Huang ◽

Bo Wei ◽

Xiaosong Wu ◽

Hongqing Xi ◽

...

Keyword(s):

Gastric Cancer ◽

Precision Medicine ◽

Therapeutic Strategies

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Basic Overview of Current Immunotherapy Approaches in Cancer

American Society of Clinical Oncology Educational Book ◽

10.1200/edbk_156572 ◽

2016 ◽

pp. 298-308 ◽

Cited By ~ 12

Author(s):

Vamsidhar Velcheti ◽

Kurt Schalper

Keyword(s):

Immune Evasion ◽

Immune Checkpoint ◽

Immune Checkpoint Blockade ◽

Therapeutic Strategies ◽

Checkpoint Blockade ◽

Basic Principles ◽

The Past ◽

Recent Success

Recent success of immunotherapy strategies such as immune checkpoint blockade in several malignancies has established the role of immunotherapy in the treatment of cancer. Cancers use multiple mechanisms to co-opt the host-tumor immune interactions, leading to immune evasion. Our understanding of the host-tumor interactions has evolved over the past few years and led to various promising new therapeutic strategies. This article will focus on the basic principles of immunotherapy, novel pathways/agents, and combinatorial immunotherapies.

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