Gene signature of antigen processing and presentation machinery predicts response to checkpoint blockade in non-small cell lung cancer (NSCLC) and melanoma

Thompson, Jeffrey C.; Davis, Christiana; Deshpande, Charuhas; Hwang, Wei–Ting; Jeffries, Seth; Huang, Alexander C.; Mitchell, Tara C.; Langer, Corey J.; Albelda, Steven Μ.

doi:10.1136/jitc-2020-000974

Cited by 62 publications

(54 citation statements)

References 51 publications

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“…The major functions of the YTH family seem to point in the direction of immunomodulation, especially antigen processing and presentation. This was in accordance with the finding of a published paper, showing that gene signature of antigen processing and presentation machinery may predict the therapeutic effect of immune checkpoint inhibitors such as anti-PD-1/PD-L1 [ 42 ]. Another study gave a similar conclusion that impaired antigen processing and presentation may account for the acquired resistance of immune checkpoint inhibitors and thus led to treatment failure [ 43 ] in lung cancer.…”

Section: Discussionsupporting

confidence: 92%

Comprehensive Analysis of YTH Domain Family in Lung Adenocarcinoma: Expression Profile, Association with Prognostic Value, and Immune Infiltration

Yao

Yan

et al. 2021

Disease Markers

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Background. All YTH domain family members are m6A reader proteins accounting for the methylation modulation involved in the process of tumorgenesis and tumor progression. However, the expression profiles and roles of the YTH domain family in lung adenocarcinoma (LUAD) remain to be further illustrated. Methods. GEPIA2 and TNMplot databases were used to generate the expression profiles of the YTH family. Kaplan-Meier plotter database was employed to analysis the prognostic value of the YTH family. Coexpression profiles and genetic alterations analysis of the YTH family were undertaken using the cBioPortal database. YTH family protein-associated protein-protein interaction (PPI) network was identified by using STRING. Functional enrichment analysis was performed with the help of the WebGestalt database. The correlation analysis between the YTH family and immune cell infiltration in LUAD was administrated by using the TIMER2.0 database. Results. mRNA expression of YTHDC1 and YTHDC2 was significantly lower in LUAD, whereas YTHDF1, YTHDF2, and YTHDF3 with apparently higher expression. YTHDF2 expression was observed to be the highest in the nonsmoker subgroup, and its expression gradually decreased with the increased severity of smoking habit. LUAD patients with low expression of YTHDC2, YTHDF1, and YTHDF2 were correlated with a better overall survival (OS) time. The YTHDF1 genetic alteration rate was 26%, which was the highest in the YTH family. The major cancer-associated functions of YTH family pointed in the direction of immunomodulation, especially antigen processing and presentation. Most of the YTH family members were significantly correlated with the infiltration of CD4+ T cells, CD8+ T cells, macrophages, and neutrophils, indicating the deep involvement of the YTH domain family in the immune cell infiltration in LUAD. Conclusion. The molecular and expression profiles of the YTH family were dysregulated in LUAD. YTH family members (especially YTHDC2) were promising biomarkers and potential therapeutic targets that may bring benefit for the patients with LUAD.

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Section: Discussionsupporting

confidence: 92%

Comprehensive Analysis of YTH Domain Family in Lung Adenocarcinoma: Expression Profile, Association with Prognostic Value, and Immune Infiltration

Yao

Yan

et al. 2021

Disease Markers

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“…Interestingly, such morphological changes have been also reported before, Chae et al have shown a “spindle-like” and fibroblastic morphologic change in BEAS-2B cells and a loss of epithelial cell markers and a gain of mesenchymal cell markers in the case of non-small cell lung cancer (NSCLC) research [ 43 ]. Treatment with MWCNTs, accompanied with morphological changes, decreased E-cadherin at the mRNA and protein level, which is a hallmark of EMT [ 21 , 23 ]. Globally, the expression of mesenchymal markers N-cadherin, Vimentin and Fibronectin was increased, which supports the implementation of this process [ 22 , 24 ].…”

Section: Discussionmentioning

confidence: 99%

“…DNA damages as well as abnormal mitoses are events that can promote the initiation of carcinogenesis. In this multi-step process, it was demonstrated that the epithelial-mesenchymal transition (EMT) takes place in neoplastic cells that have previously undergone genetic or epigenetic changes in oncogenes and tumour suppressor genes [ 21 , 22 , 23 ]. EMT is known to be a reversible and dynamic cellular program whereby epithelial cells progressively become mesenchymatous [ 24 , 25 ].…”

Section: Introductionmentioning

confidence: 99%

“…EMT is known to be a reversible and dynamic cellular program whereby epithelial cells progressively become mesenchymatous [ 24 , 25 ]. This conversion involves deep phenotypic remodelling, accompanied by a switch in gene expression from “epithelial genes” such as E-cadherin ( cdh1 ), to “mesenchymal genes”, such as N-cadherin ( cdh2 ), Vimentin ( vim ), or Fibronectin ( fn1 ) [ 21 ]. This transition can occur because of genetic modification, in response to cellular stress or DNA damage, but also as a result of inflammation and the initiation of a fibrotic process.…”

Section: Introductionmentioning

confidence: 99%

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Continuous Long-Term Exposure to Low Concentrations of MWCNTs Induces an Epithelial-Mesenchymal Transition in BEAS-2B Cells

et al. 2021

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In the field of nanotechnology, the use of multi-walled carbon nanotubes (MWCNTs) is growing. Pulmonary exposure during their production, use, and handling is raising concerns about their potential adverse health effects. The purpose of this study is to assess how the physical characteristics of MWCNTs, such as diameter and/or length, can play a role in cellular toxicity. Our experimental design is based on the treatment of human bronchial epithelial cells (BEAS-2B) for six weeks with low concentrations (0.125–1 µg/cm2) of MWCNTs having opposite characteristics: NM-403 and Mitsui-7. Following treatment with both MWCNTs, we observed an increase in mitotic abnormalities and micronucleus-positive cells. The cytotoxic effect was delayed in cells treated with NM-403 compared to Mitsui-7. After 4–6 weeks of treatment, a clear cellular morphological change from epithelial to fibroblast-like phenotype was noted, together with a change in the cell population composition. BEAS-2B cells underwent a conversion from the epithelial to mesenchymal state as we observed a decrease in the epithelial marker E-cadherin and an increased expression of mesenchymal markers N-cadherin, Vimentin, and Fibronectin. After four weeks of recovery, we showed that the induced epithelial-mesenchymal transition is reversible, and that the degree of reversibility depends on the MWCNT.

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“…Therefore, it is predicted that reversal of EMT may improve the resistance to anti-PD-1/PD-L1 therapy [ 65 ]. Further study found that in the same NSCLC cohort, the eight genes associated with antigen processing machinery (APM) scores could more effectively predict the efficacy than inflammation scores [ 66 ]. Also, our previous study indicated that some immune response-related signatures related to the efficacy of immune checkpoint inhibitor in lung adenocarcinoma [ 4 ].…”

Section: Tumor Feature Related Biomarkersmentioning

confidence: 99%

Predictive biomarkers of anti-PD-1/PD-L1 therapy in NSCLC

Niu

et al. 2021

Exp Hematol Oncol

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Immunotherapy, especially anti-programmed cell death protein 1/programmed cell death ligand 1 (PD-1/PD-L1) treatment has significantly improved the survival of non-small cell lung cancer (NSCLC) patients. However, the overall response rate remains unsatisfactory. Many factors affect the outcome of anti-PD-1/PD-L1 treatment, such as PD-L1 expression level, tumor-infiltrating lymphocytes (TILs), tumor mutation burden (TMB), neoantigens, and driver gene mutations. Further exploration of biomarkers would be favorable for the best selection of patients and precisely predict the efficacy of anti-PD-1/PD-L1 treatment. In this review, we summarized the latest advances in this field, and discussed the potential applications of these laboratory findings in the clinic.

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Gene signature of antigen processing and presentation machinery predicts response to checkpoint blockade in non-small cell lung cancer (NSCLC) and melanoma

Cited by 62 publications

References 51 publications

Comprehensive Analysis of YTH Domain Family in Lung Adenocarcinoma: Expression Profile, Association with Prognostic Value, and Immune Infiltration

Comprehensive Analysis of YTH Domain Family in Lung Adenocarcinoma: Expression Profile, Association with Prognostic Value, and Immune Infiltration

Continuous Long-Term Exposure to Low Concentrations of MWCNTs Induces an Epithelial-Mesenchymal Transition in BEAS-2B Cells

Predictive biomarkers of anti-PD-1/PD-L1 therapy in NSCLC

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