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Single-cell analysis of T lymphocytes infiltrating colorectal carcinoma: the dilemma of specificity.Oncoimmunology 2024Advances in single-cell RNA and T cell receptor (TCR) sequencing allow to study the specificity and functionality of tumor-infiltrating T lymphocytes. A recent study...
Advances in single-cell RNA and T cell receptor (TCR) sequencing allow to study the specificity and functionality of tumor-infiltrating T lymphocytes. A recent study unravels fundamental differences between microsatellite-instable (MSI) colorectal cancers, in which T cells tend to be tumor-specific, and microsatellite-stable (MSS) cancers, in which T cells exhibit bystander features.
Topics: Humans; T-Lymphocytes; Single-Cell Analysis; Lymphocytes, Tumor-Infiltrating; Microsatellite Instability; Colorectal Neoplasms
PubMed: 38192442
DOI: 10.1080/2162402X.2023.2300520 -
Journal of Clinical Oncology : Official... Aug 2022Immunotherapy (IO) agents have led to significant improvements in patient outcomes across many tumor types. There have been great efforts to introduce immune checkpoint... (Review)
Review
Immunotherapy (IO) agents have led to significant improvements in patient outcomes across many tumor types. There have been great efforts to introduce immune checkpoint inhibitors into the treatment paradigm of esophagogastric cancers as well. A number of randomized phase III trials, which will be reviewed here, established the role of these agents in both early-stage and advanced-stage disease. Adjuvant nivolumab is US Food and Drug Administration-approved after neoadjuvant chemoradiation and resection of esophageal and gastroesophageal junction cancers on the basis of the phase III CheckMate 577 trial. In the advanced setting, patients with programmed death receptor ligand-1-positive tumors should be recommended IO in combination with chemotherapy in the first-line setting on the basis of the results from KEYNOTE 590, CheckMate 649, and CheckMate 648. Across trials, chemotherapy continues to play a critical role in the first-line setting and should be offered to all patients who are eligible for systemic therapy, including those with biomarker select tumors. In the later lines of treatment, IO has modest activity, and prior studies have grown largely irrelevant because of the enrollment of IO-naive patients. Similar to other disease types, patients with microsatellite unstable (microsatellite instability high) tumors represent a unique cohort that is more sensitive to IO. However, there are no randomized studies evaluating how best to apply IO in early or advanced stages specifically for the treatment of patients with microsatellite instability high upper GI tumors. Questions remain how to best select patients who benefit from IO treatments, how to augment IO activity in programmed death receptor ligand-1-negative tumors, and how to incorporate IO in late-line settings or for recurrent disease that has been treated with IO-containing regimens during early stages.
Topics: Esophageal Neoplasms; Humans; Immunotherapy; Ligands; Microsatellite Instability; Receptors, Death Domain; Stomach Neoplasms
PubMed: 35839430
DOI: 10.1200/JCO.21.02500 -
European Journal of Human Genetics :... Sep 2022
Topics: Brazil; Colorectal Neoplasms; Gastrointestinal Neoplasms; Humans; Microsatellite Instability; Stomach Neoplasms
PubMed: 35726018
DOI: 10.1038/s41431-022-01134-6 -
Frontiers in Immunology 2022Colon adenocarcinoma (COAD) is a prevalent malignancy that causes significant mortality. Microsatellite instability plays a pivotal function in COAD development and...
BACKGROUND
Colon adenocarcinoma (COAD) is a prevalent malignancy that causes significant mortality. Microsatellite instability plays a pivotal function in COAD development and immunotherapy resistance. However, the detailed underlying mechanism requires further investigation. Consequently, identifying molecular biomarkers with prognostic significance and revealing the role of MSI in COAD is important for addressing key obstacles in the available treatments.
METHODS
CIBERSORT and ESTIMATE analyses were performed to evaluate immune infiltration in COAD samples, followed by correlation analysis for MSI and immune infiltration. Then, differentially expressed genes (DEGs) in MSI and microsatellite stability (MSS) samples were identified and subjected to weighted gene co-expression network analysis (WGCNA). A prognostic model was established with univariate cox regression and LASSO analyses, then evaluated with Kaplan-Meier analysis. The correlation between the prognostic model and immune checkpoint inhibitor (ICI) response was also analyzed.
RESULTS
In total, 701 significant DEGs related to MSI status were identified, and WGCNA revealed two modules associated with the immune score. Then, a seven-gene prognostic model was constructed using LASSO and univariate cox regression analyses to predict survival and ICI response. The high-risk score patients in TCGA and GEO cohorts presented a poor prognosis, as well as a high immune checkpoint expression, so they are more likely to benefit from ICI treatment.
CONCLUSION
The seven-gene prognostic model constructed could predict the survival of COAD and ICI response and serve as a reference for immunotherapy decisions.
Topics: Humans; Prognosis; Microsatellite Instability; Colonic Neoplasms; Adenocarcinoma; Immune Checkpoint Inhibitors; Biomarkers, Tumor
PubMed: 36275690
DOI: 10.3389/fimmu.2022.988303 -
Pathology Oncology Research : POR 2024Current clinical guidelines recommend mismatch repair (MMR) protein immunohistochemistry (IHC) or molecular microsatellite instability (MSI) tests as predictive markers... (Review)
Review
Current clinical guidelines recommend mismatch repair (MMR) protein immunohistochemistry (IHC) or molecular microsatellite instability (MSI) tests as predictive markers of immunotherapies. Most of the pathological guidelines consider MMR protein IHC as the gold standard test to identify cancers with MMR deficiency and recommend molecular MSI tests only in special circumstances or to screen for Lynch syndrome. However, there are data in the literature which suggest that the two test types may not be equal. For example, molecular epidemiology studies reported different rates of deficient MMR (dMMR) and MSI in various cancer types. Additionally, direct comparisons of the two tests revealed relatively frequent discrepancies between MMR IHC and MSI tests, especially in non-colorectal and non-endometrial cancers and in cases with unusual dMMR phenotypes. There are also scattered clinical data showing that the efficacy of immune checkpoint inhibitors is different if the patient selection was based on dMMR versus MSI status of the cancers. All these observations question the current dogma that dMMR phenotype and genetic MSI status are equal predictive markers of the immunotherapies.
Topics: Humans; Microsatellite Instability; DNA Mismatch Repair; Biomarkers, Tumor; Neoplasms; Prognosis
PubMed: 38655493
DOI: 10.3389/pore.2024.1611719 -
Journal of Cancer Research and Clinical... Dec 2023We recently showed that low microsatellite instability (MSI-L) is associated with a good response to platinum/5-fluorouracil (5-FU) neoadjuvant chemotherapy (CTx) in...
PURPOSE
We recently showed that low microsatellite instability (MSI-L) is associated with a good response to platinum/5-fluorouracil (5-FU) neoadjuvant chemotherapy (CTx) in gastric cancer. The purpose of this study was to characterize the instability pattern and to investigate an association of MSI-L tumors with mutations in genes of DNA repair pathways and with total tumor mutation burden (TMB).
METHODS
MSI patterns were compared between 67 MSI high (-H) and 35 MSI-L tumors. Whole-exome sequencing was performed in 34 microsatellite stable (MSS) and 20 MSI-L tumors after or without neoadjuvant CTx.
RESULTS
Of the 35 MSI-L tumors, 33 tumors had instability at a dinucleotide repeat marker. In the homologous recombination (HR) pathway, 10 of the 34 (29%) MSS and 10 of the 20 (50%) MSI-L tumors showed variants (p = 0.154). In the DNA damage tolerance pathway, 6 of the 34 (18%) MSS and 7 of the 20 (35%) MSI-L tumors had variants (p = 0.194). The HR deficiency score was similar in both tumor groups. TMB was significantly higher in MSI-L compared to MSS tumors after CTx (p = 0.046). In the MSS and MSI-L tumors without CTx no difference was observed (p = 1.00).
CONCLUSION
MSI-L due to instability at dinucleotide repeat markers was associated with increased TMB after neoadjuvant CTx treatment, indicating sensitivity to platinum/5-FU CTx. If confirmed in further studies, this could contribute to refined chemotherapeutic options including immune-based strategies for GC patients with MSI-L tumors.
Topics: Humans; Stomach Neoplasms; Microsatellite Instability; Platinum; Fluorouracil; Mutation; Microsatellite Repeats
PubMed: 37819581
DOI: 10.1007/s00432-023-05430-6 -
European Journal of Obstetrics,... Jul 2022Infertility is associated to multiple types of different genomic instabilities and is a genetic feature of genomic instability syndromes. While the mismatch repair... (Review)
Review
Infertility is associated to multiple types of different genomic instabilities and is a genetic feature of genomic instability syndromes. While the mismatch repair machinery contributes to the maintenance of genome integrity, surprisingly its potential role in infertility is overlooked. Defects in mismatch repair mechanisms contribute to microsatellite instability and genomic instability syndromes, due to the inability to repair newly replicated DNA. This article reviews the literature to date to elucidate the contribution of microsatellite instability to genomic instability syndromes and infertility. The key findings presented reveal microsatellite instability is poorly researched in genomic instability syndromes and infertility.
Topics: DNA Mismatch Repair; Genomic Instability; Humans; Infertility; Microsatellite Instability; Microsatellite Repeats; Syndrome
PubMed: 35671666
DOI: 10.1016/j.ejogrb.2022.06.001 -
Oncology 2022Nonampullary duodenal adenocarcinoma (NADA) is a rare disease. Although several prognostic factors have been reported for this disease, they remain controversial due to...
PURPOSE
Nonampullary duodenal adenocarcinoma (NADA) is a rare disease. Although several prognostic factors have been reported for this disease, they remain controversial due to their rarity. In this study, we retrospectively analyzed 54 cases of invasive NADA, focusing on the microsatellite instability (MSI) phenotype, programmed cell death-ligand 1 (PD-L1) expression, and prognostic factors.
METHODS
Expression of the PD-L1 protein and cell differentiation markers in tumors was detected by immunohistochemistry. Microsatellite markers (NR-21, NR-22, NR-24, BAT-25, and BAT-26) were amplified for MSI assessment by PCR.
RESULTS
The incidence of MSI in invasive NADA was 35.2%. No significant correlation between the MSI phenotype and clinicopathological factors was observed. Positive expression of PD-L1 by immune cells was common in advanced-stage disease (p = 0.054), and positive expression of PD-L1 in cancer cells correlated significantly with the histologically undifferentiated type (p = 0.016). Kaplan-Meier survival analysis demonstrated a significantly better overall survival (OS) in patients with MSI (p = 0.013) and at early-stage disease (p = 0.000) than in those with microsatellite-stable or at late tumor stages. Univariate and multivariate analyses showed that MSI (hazard ratio [HR]: 0.282, 95% confidence interval [CI]: 0.106-0.751, p = 0.011) and early tumor stage (stage I-II) (HR: 8.81, 95% CI: 2.545-30.500, p = 0.001) were independent better prognostic factors of OS.
CONCLUSIONS
MSI and early tumor stage (stage I-II) were independent better prognostic factors of OS. A high proportion of MSI phenotypes and positive PD-L1 expression may be helpful for identifying immune checkpoint inhibitors as a novel therapeutic strategy.
Topics: Adenocarcinoma; B7-H1 Antigen; Biomarkers, Tumor; Humans; Microsatellite Instability; Prognosis; Retrospective Studies
PubMed: 35350032
DOI: 10.1159/000519805 -
Frontiers in Immunology 2023Colorectal cancer (CRC) is the second leading cause of cancer-related deaths worldwide, and its incidence continues to rise, particularly in developing countries. The... (Review)
Review
Colorectal cancer (CRC) is the second leading cause of cancer-related deaths worldwide, and its incidence continues to rise, particularly in developing countries. The advent of immune checkpoint inhibitors (ICIs) has represented a significant advancement in CRC treatment. Deficient mismatch repair (dMMR) or high microsatellite instability (MSI-H) serves as a biomarker for immunotherapy, with dMMR/MSI-H CRC exhibiting significantly better response rates to immunotherapy compared to proficient mismatch repair (pMMR)or microsatellite stable (MSS) CRC. While some progress has been made in the treatment of pMMR/MSS CRC in recent years, it remains a challenging issue in clinical practice. The tumor microenvironment (TME) plays a crucial role not only in the development and progression of CRC but also in determining the response to immunotherapy. Understanding the characteristics of the TME in pMMR/MSS CRC could offer new insights to enhance the efficacy of immunotherapy. In this review, we provide an overview of the current research progress on the TME characteristics and advancements in immunotherapy for pMMR/MSS CRC.
Topics: Humans; Immunotherapy; Colorectal Neoplasms; DNA Mismatch Repair; Immune Checkpoint Inhibitors; Microsatellite Instability; Microsatellite Repeats; Tumor Microenvironment
PubMed: 38187388
DOI: 10.3389/fimmu.2023.1298524 -
Nature Communications Nov 2023Mismatch Repair Deficiency (dMMR)/Microsatellite Instability (MSI) is a key biomarker in colorectal cancer (CRC). Universal screening of CRC patients for MSI status is...
Mismatch Repair Deficiency (dMMR)/Microsatellite Instability (MSI) is a key biomarker in colorectal cancer (CRC). Universal screening of CRC patients for MSI status is now recommended, but contributes to increased workload for pathologists and delayed therapeutic decisions. Deep learning has the potential to ease dMMR/MSI testing and accelerate oncologist decision making in clinical practice, yet no comprehensive validation of a clinically approved tool has been conducted. We developed MSIntuit, a clinically approved artificial intelligence (AI) based pre-screening tool for MSI detection from haematoxylin-eosin (H&E) stained slides. After training on samples from The Cancer Genome Atlas (TCGA), a blind validation is performed on an independent dataset of 600 consecutive CRC patients. Inter-scanner reliability is studied by digitising each slide using two different scanners. MSIntuit yields a sensitivity of 0.96-0.98, a specificity of 0.47-0.46, and an excellent inter-scanner agreement (Cohen's κ: 0.82). By reaching high sensitivity comparable to gold standard methods while ruling out almost half of the non-MSI population, we show that MSIntuit can effectively serve as a pre-screening tool to alleviate MSI testing burden in clinical practice.
Topics: Humans; Microsatellite Instability; Artificial Intelligence; Reproducibility of Results; Early Detection of Cancer; Colorectal Neoplasms; DNA Mismatch Repair
PubMed: 37932267
DOI: 10.1038/s41467-023-42453-6