scholarly journals NOTCH3 is a Prognostic Factor and Is Correlated With Immune Tolerance in Gastric Cancer

2021 ◽  
Vol 10 ◽  
Author(s):  
Yuehong Cui ◽  
Qian Li ◽  
Wei Li ◽  
Yan Wang ◽  
Fang Lv ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Prognostic Factor ◽  
Immune Tolerance ◽  
Immune Checkpoint ◽  
Prognostic Value ◽  
Checkpoint Inhibitors ◽  
Prognostic Significance ◽  
Predictive Biomarkers ◽  
The Cancer Genome Atlas ◽  
Km Plotter

IntroductionAlthough traditional treatments confer survival benefits to patients with gastric cancer (GC), many patients experience relapse soon after postoperative adjuvant therapy. Immune-related mechanisms play an important role in GC, and immunotherapeutic strategies are considered to be a promising direction for the treatment of GC. Thus, our study aimed to investigate the expression and prognostic significance of immune-related genes in GC.MethodsFormalin-fixed, paraffin-embedded samples were collected from 48 resectable GC patients. The transcriptome data of the tumor immune microenvironment were assessed using an immuno-oncology 395-gene panel RNA sequencing platform. The prognostic value of the 395 genes was analyzed and validated in the KM plotter and GEPIA databases. The data from The Cancer Genome Atlas (TCGA, downloaded from UCSC Xena repository) and Tumor IMmune Estimation Resource (TIMER) were used to evaluate the correlations between prognostic factors and immune signatures.ResultsAmong the 395 genes, NOTCH3 was identified as a good prognostic factor for GC patients. Its prognostic value was also suggested in both our GC cohort from Zhongshan Hospital and the public databases (KM plotter and GEPIA database). Mechanistically, high NOTCH3 expression correlated with a lower infiltration of activated CD8+ T cells and a higher infiltration of immunosuppressive cells including Tregs and M2 macrophages in the tumor microenvironment. Moreover, high NOTCH3 expression was accompanied by the increased expression of a series of immune checkpoint inhibitors, resulting in a dampened immune response. Interestingly, NOTCH3 expression had a negative association with well-documented predictive biomarkers of immune checkpoint blockade (ICB) immunotherapy, including tumor mutation burden (TMB), gene expression profiling (GEP) score and innate anti-PD-1 resistance (IPRES) signature.ConclusionThese findings uncovered a new mechanism by which NOTCH3 participates in the immune tolerance of GC, implying the potential of NOTCH3 as a therapeutic target or predictive marker for GC patients.

scholarly journals How to Best Exploit Immunotherapeutics in Advanced Gastric Cancer: Between Biomarkers and Novel Cell-Based Approaches

2021 ◽  
Vol 10 (7) ◽  
pp. 1412
Author(s):  
Michele Ghidini ◽  
Angelica Petrillo ◽  
Andrea Botticelli ◽  
Dario Trapani ◽  
Alessandro Parisi ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Advanced Gastric Cancer ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitor ◽  
Checkpoint Inhibitors ◽  
Predictive Biomarkers ◽  
Clinical Implementation ◽  
T Cell Therapy ◽  
Dismal Prognosis

Despite extensive research efforts, advanced gastric cancer still has a dismal prognosis with conventional treatment options. Immune checkpoint inhibitors have revolutionized the treatment landscape for many solid tumors. Amongst gastric cancer subtypes, tumors with microsatellite instability and Epstein Barr Virus positive tumors provide the strongest rationale for responding to immunotherapy. Various predictive biomarkers such as mismatch repair status, programmed death ligand 1 expression, tumor mutational burden, assessment of tumor infiltrating lymphocytes and circulating biomarkers have been evaluated. However, results have been inconsistent due to different methodologies and thresholds used. Clinical implementation therefore remains a challenge. The role of immune checkpoint inhibitors in gastric cancer is emerging with data from monotherapy in the heavily pre-treated population already available and studies in earlier disease settings with different combinatorial approaches in progress. Immune checkpoint inhibitor combinations with chemotherapy (CT), anti-angiogenics, tyrosine kinase inhibitors, anti-Her2 directed therapy, poly (ADP-ribose) polymerase inhibitors or dual checkpoint inhibitor strategies are being explored. Moreover, novel strategies including vaccines and CAR T cell therapy are also being trialed. Here we provide an update on predictive biomarkers for response to immunotherapy with an overview of their strengths and limitations. We discuss clinical trials that have been reported and trials in progress whilst providing an account of future steps needed to improve outcome in this lethal disease.

scholarly journals New drug developments in metastatic gastric cancer

2018 ◽  
Vol 11 ◽  
pp. 175628481880807 ◽  
Author(s):  
Aaron C. Tan ◽  
David L. Chan ◽  
Wasek Faisal ◽  
Nick Pavlakis
Keyword(s):  
Gastric Cancer ◽  
Clinical Trials ◽  
Targeted Therapies ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Treatment Options ◽  
Predictive Biomarkers ◽  
Metastatic Gastric Cancer ◽  
New Era

Metastatic gastric cancer is associated with a poor prognosis and novel treatment options are desperately needed. The development of targeted therapies heralded a new era for the management of metastatic gastric cancer, however results from clinical trials of numerous targeted agents have been mixed. The advent of immune checkpoint inhibitors has yielded similar promise and results from early trials are encouraging. This review provides an overview of the systemic treatment options evaluated in metastatic gastric cancer, with a focus on recent evidence from clinical trials for targeted therapies and immune checkpoint inhibitors. The failure to identify appropriate predictive biomarkers has hampered the success of many targeted therapies in gastric cancer, and a deeper understanding of specific molecular subtypes and genomic alterations may allow for more precision in the application of novel therapies. Identifying appropriate biomarkers for patient selection is essential for future clinical trials, for the most effective use of novel agents and in combination approaches to account for growing complexity of treatment options.

scholarly journals Current status and future potential of predictive biomarkers for immune checkpoint inhibitors in gastric cancer

ESMO Open ◽  
2020 ◽  
Vol 5 (4) ◽  
pp. e000791 ◽  
Author(s):  
Byung Woog Kang ◽  
Ian Chau
Keyword(s):  
Gastric Cancer ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Gene Expression Signature ◽  
Predictive Biomarkers ◽  
Predictive Biomarker ◽  
Metastatic Gastric Cancer ◽  
Scientific Data ◽  
Current Status

Immunotherapy is revolutionising cancer treatment and has already emerged as standard treatment for patients with recurrent or metastatic gastric cancer (GC). Recent research has been focused on identifying robust predictive biomarkers for GC treated with immune checkpoint inhibitors (ICIs). The expression of programmed cell death protein-ligand-1 (PD-L1) is considered a manifestation of immune response evasion, and several studies have already reported the potential of PD-L1 expression as a predictive parameter for various human malignancies. Meanwhile, based on comprehensive molecular characterisation of GC, testing for Epstein-Barr virus and microsatellite instability is a potential predictive biomarker. Culminating evidence suggests that novel biomarkers, such as the tumour mutational burden and gene expression signature, could indicate the success of treatment with ICIs. However, the exact roles of these biomarkers in GC treated with ICIs remain unclear. Therefore, this study reviews recent scientific data on current and emerging biomarkers for ICIs in GC, which have potential to improve treatment outcomes.

Progress and prospects of immune checkpoint inhibitors in advanced gastric cancer

2021 ◽  
Author(s):  
Zhu Zeng ◽  
Biao Yang ◽  
Zhengyin Liao
Keyword(s):  
Gastric Cancer ◽  
Signaling Pathways ◽  
Advanced Gastric Cancer ◽  
Immune Checkpoint ◽  
Conventional Therapy ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Predictive Biomarkers ◽  
Significant Survival ◽  
The Way

Gastric cancer, a digestive malignancy, is the sixth most frequent cancer and the second leading cause of tumor-related deaths worldwide. The emergence and advancement of immunotherapeutic agents has brought significant survival benefits for patients with gastric cancer and increasingly challenged the conventional therapy pattern involving chemotherapy and target drugs. Furthermore, these breakthroughs have paved the way for immunotherapy, especially with immune checkpoint inhibitors, which act by blocking specific signaling pathways, in particular the CTLA4 pathway and the PD-1/PD-L1 pathway. In this review we summarize the current trials of immune checkpoint inhibitors in GC and their predictive biomarkers, and discuss their present limitations.

Prevalence of prkdc mutations and association with response to immune checkpoint inhibitors in solid tumors.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. e15250-e15250
Author(s):  
Yi Li ◽  
Chuan-ben Chen ◽  
Yu Chen ◽  
Yan-Fang Guan ◽  
Yingying Huang ◽  
...  
Keyword(s):  
Solid Tumor ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Cox Regression ◽  
Checkpoint Inhibitors ◽  
Predictive Biomarkers ◽  
Predictive Biomarker ◽  
The Cancer Genome Atlas ◽  
Wild Type ◽  
Sequencing Data

e15250 Background: Predictive biomarkers of response to immune checkpoint inhibitors (ICIs) help to identify cancer patients who will benefit from immunotherapy. PRKDC is an important gene relates to DNA double-strand break (DSB) repair and central T-cell tolerance. We aim to investigate the association between PRKDC mutations and tumor mutation burden (TMB), tumor microenvironments (TME), and response to ICIs. Methods: The whole exome sequencing data of 4022 solid tumor samples from the Cancer Genome Atlas (TCGA) and the panel-based sequencing data of 4652 solid tumor samples from GenePlus-Beijing, China were used to analyze TMB. The mRNA expression data of 3541 solid tumor samples from TCGA was used to explore the effect of PRKDC mutation on TME. Four ICIs-treated cohorts were analyzed for verifying the correlation between PRKDC mutation and the response to ICIs. Results: In TCGA datasets and GenePlus datasets, we both found that the TMB in PRKDC mutation samples were significantly higher than PRKDC wild-type samples(P < 0.05, P<0.0001 respectively). When compare to other pivotal DNA damage response (DDR) genes, it showed an identical effect of the degree in TMB by PRKDC mutation with MMR ( PMS2/ MLH1/ MSH2/ MSH6) genes, POLE/D1 and BRCA1/2 mutation (P > 0.05). Further, in TCGA datasets, it showed that PRKDC mutation samples were associated with significant expression increase of CD8+ T cells, NK cells, immune-checkpoint, chemokines etc compared to PRKDC wild-type samples (P < 0.05). In ICIs-treated cohorts, we also found the PRKDC mutation was associated with superior survival(median PFS, not reached (NR) vs. 6.8 months HR, 0.2893 95% CI, 0.1255-0.6672 P = 0.0650, Hellmann cohort; median OS, 1184 days vs. 250 days HR, 0.5126 95% CI, 0.2715-0.9679 P = 0.1020, Allen cohort), and the superiority was significantly in multivariate Cox regression analyses (HR, 0.361 95% CI,0.155-0.841; P = 0.018, Allen cohort; HR, 0.240 95% CI,0.058-0.998; P = 0.050, Hellmann cohort). Conclusions: PRKDC mutations are associated with an increased TMB, an inflamed TME and a better response to ICIs, it may be a potential predictive biomarker for ICIs-immunotherapy.

scholarly journals Evaluation of the prognostic value of CBXs in gastric cancer patients

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Mengya He ◽  
Limin Yue ◽  
Haiyan Wang ◽  
Feiyan Yu ◽  
Mingyang Yu ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Target Genes ◽  
Prognostic Significance ◽  
Disease Free Survival ◽  
Genetic Alterations ◽  
Genetic Mutation ◽  
The Cancer Genome Atlas ◽  
Normal Tissues ◽  
Interactive Analysis ◽  
Gastric Cancer Patients

AbstractChromobox (CBX) proteins were suggested to exert epigenetic regulatory and transcriptionally repressing effects on target genes and might play key roles in the carcinogenesis of a variety of carcinomas. Nevertheless, the functions and prognostic significance of CBXs in gastric cancer (GC) remain unclear. The current study investigated the roles of CBXs in the prognosis of GC using the Oncomine, The Gene Expression Profiling Interactive Analysis (GEPIA), UALCAN, The Cancer Genome Atlas (TCGA), and cBioPortal databases. CBX1/2/3/4/5 were significantly upregulated in GC tissues compared with normal tissues, and CBX7 was downregulated. Multivariate analysis showed that high mRNA expression levels of CBX3/8 were independent prognostic factors for prolonged OS in GC patients. In addition, the genetic mutation rate of CBXs was 37% in GC patients, and genetic alterations in CBXs showed no association with OS or disease-free survival (DFS) in GC patients. These results indicated that CBX3/8 can be prognostic biomarkers for the survival of GC patients.

scholarly journals Emerging Trends for Radio-Immunotherapy in Rectal Cancer

Cancers ◽  
2021 ◽  
Vol 13 (6) ◽  
pp. 1374
Author(s):  
Claudia Corrò ◽  
Valérie Dutoit ◽  
Thibaud Koessler
Keyword(s):  
Rectal Cancer ◽  
Tumor Microenvironment ◽  
Immune Checkpoint ◽  
Checkpoint Inhibitors ◽  
Predictive Biomarkers ◽  
Tumor Infiltrating Lymphocytes ◽  
T Cell Infiltration ◽  
Emerging Trends ◽  
Tumor Mutational Burden ◽  
Microsatellite Stability

Rectal cancer is a heterogeneous disease at the genetic and molecular levels, both aspects having major repercussions on the tumor immune contexture. Whilst microsatellite status and tumor mutational load have been associated with response to immunotherapy, presence of tumor-infiltrating lymphocytes is one of the most powerful prognostic and predictive biomarkers. Yet, the majority of rectal cancers are characterized by microsatellite stability, low tumor mutational burden and poor T cell infiltration. Consequently, these tumors do not respond to immunotherapy and treatment largely relies on radiotherapy alone or in combination with chemotherapy followed by radical surgery. Importantly, pre-clinical and clinical studies suggest that radiotherapy can induce a complete reprograming of the tumor microenvironment, potentially sensitizing it for immune checkpoint inhibition. Nonetheless, growing evidence suggest that this synergistic effect strongly depends on radiotherapy dosing, fractionation and timing. Despite ongoing work, information about the radiotherapy regimen required to yield optimal clinical outcome when combined to checkpoint blockade remains largely unavailable. In this review, we describe the molecular and immune heterogeneity of rectal cancer and outline its prognostic value. In addition, we discuss the effect of radiotherapy on the tumor microenvironment, focusing on the mechanisms and benefits of its combination with immune checkpoint inhibitors.

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