Molecular correlates and therapeutic targets in T cell-inflamed versus non-T cell-inflamed tumors across cancer types

Bao, Riyue; Luke, Jason J.

doi:10.1101/773127

Cited by 6 publications

(7 citation statements)

References 51 publications

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“…We used a previously described T-cell inflammation score, 11 which correlates with other validated interferon-g gene signatures (Appendix). 12 This trial is registered with Clin-icalTrials.gov identifier: NCT02743819. The trial is closed to enrollment, but patients remain on treatment and in observation for safety and ongoing response assessments.…”

Section: Discussionmentioning

confidence: 99%

“…Patients with active CNS metastases were excluded (previously treated, stable CNS disease allowed); no prior anti-CTLA-4 antibody use in the metastatic setting was permitted. Full inclusion and exclusion criteria are listed in the study Protocol (online only [pp [12][13][14][15]). The study Protocol was reviewed and approved by the appropriate institutional review boards at each participating site.…”

Section: Study Design and Participantsmentioning

confidence: 99%

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Pembrolizumab Plus Ipilimumab Following Anti-PD-1/L1 Failure in Melanoma

Olson

Eroglu

Brockstein

et al. 2021

JCO

Self Cite

137

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PURPOSE Combination of antiprogrammed cell death protein-1 (PD-1) plus anti–cytotoxic T-cell lymphocyte-4 (anti-CTLA-4) immunotherapy shows greater response rates (RRs) than anti-PD-1 antibody alone in melanoma, but RR after initial anti-PD-1 and programmed death ligand-1 (PD-L1) antibody progression awaits robust investigation. Anti-CTLA-4 antibody alone after anti-PD-1/L1 antibody progression has a historical RR of 13%. We report the results of the first prospective clinical trial evaluating ipilimumab 1 mg/kg plus pembrolizumab following progression on anti-PD-1 immunotherapy. METHODS Patients with advanced melanoma who had progressed on anti-PD-1/L1 antibody as immediate prior therapy (including non–anti-CTLA-4 antibody combinations) were eligible. Patients received pembrolizumab 200 mg plus ipilimumab 1 mg/kg once every 3 weeks for four doses, followed by pembrolizumab monotherapy. The primary end point was RR by irRECIST. After 35 patients, the trial met the primary end point and was expanded to enroll a total of 70 patients to better estimate the RR. RESULTS Prior treatments included 60 on anti-PD-1 antibody alone and 10 on anti-PD-1/L1 antibody–based combinations. Thirteen patients had progressed in the adjuvant setting. The median length of prior treatment with anti-PD-1/L1 antibody was 4.8 months. Response assessments included five complete and 15 partial responses, making the irRECIST RR 29% among the entire trial population. The median progression-free survival was 5.0 months, and the median overall survival was 24.7 months. The median duration of response was 16.6 months. There was no difference in median time on prior anti-PD1/L1 or time to PD1 + CTLA4 initiation between responders and nonresponders. Grade 3-4 drug-related adverse events occurred in 27% of patients. Responses occurred in PD-L1–negative, non-T-cell–inflamed, and intermediate tumor phenotypes. CONCLUSION To our knowledge, this is the first prospective study in melanoma of pembrolizumab plus low-dose ipilimumab after anti-PD-1/L1 immunotherapy failure, demonstrating significant antitumor activity and tolerability.

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Section: Discussionmentioning

confidence: 99%

Section: Study Design and Participantsmentioning

confidence: 99%

Pembrolizumab Plus Ipilimumab Following Anti-PD-1/L1 Failure in Melanoma

Olson

Eroglu

Brockstein

et al. 2021

JCO

Self Cite

137

View full text Add to dashboard Cite

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“…Absence of PTEN leads to decreased T cell infiltration in melanoma with levels of CXCL10 transcripts decreased in PTEN mutant tumors (45). Emerging evidence demonstrates that IDH1 mutations are strongly correlated with non-T cell inflamed tumors and reductions in factors such as CXCL10 (46,47).…”

Section: Many Tumor Cells Are Genomically Unstable Which Results In the Activation Of Cell Intrinsicmentioning

confidence: 99%

Dendritic Cells, the T-cell-inflamed Tumor Microenvironment, and Immunotherapy Treatment Response

Garris

Luke

2020

Clinical Cancer Research

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“…CDC1 helps activating T cells and drives INF-g secretion of CD8+T (51). Studies have found that the Wnt signaling pathway can eliminate the gradient generation of chemokines required by DC (52).…”

Section: Discussionmentioning

confidence: 99%

Nitrogen Metabolism Disorder Accelerates Occurrence and Development of Lung Adenocarcinoma: A Bioinformatic Analysis and In Vitro Experiments

et al. 2022

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BackgroundNitrogen metabolism (NM) plays a pivotal role in immune regulation and the occurrence and development of cancers. The aim of this study was to construct a prognostic model and nomogram using NM-related genes for the evaluation of patients with lung adenocarcinoma (LUAD).MethodsThe differentially expressed genes (DEGs) related to NM were acquired from The Cancer Genome Atlas (TCGA) database. Consistent clustering analysis was used to divide them into different modules, and differentially expressed genes and survival analysis were performed. The survival information of patients was combined with the expressing levels of NM-related genes that extracted from TCGA and Gene Expression Omnibus (GEO) databases. Subsequently, univariate Cox analysis and the least absolute shrinkage and selection operator (LASSO) regression were used to build a prognostic model. GO and KEGG analysis were elaborated in relation with the mechanisms of NM disorder (NMD). Meanwhile, immune cells and immune functions related to NMD were discussed. A nomogram was built according to the univariate and multivariate Cox analysis to identify independent risk factors. Finally, real-time fluorescent quantitative PCR (RT-PCR) and Western bolt (WB) were used to verify the expression level of hub genes.ResultsThere were 138 differential NM-related genes that were divided into two gene modules. Sixteen NM-related genes were used to build a prognostic model and the receiver operating characteristic curve (ROC) showed that the efficiency was reliable. GO and KEGG analysis suggested that NMD accelerated development of LUAD through the Wnt signaling pathway. The level of activated dendritic cells (aDCs) and type II interferon response in the low-risk group was higher than that of the high-risk group. A nomogram was constructed based on ABCC2, HMGA2, and TN stages, which was identified as four independent risk factors. Finally, RT-PCR and WB showed that CDH17, IGF2BP1, IGFBP1, ABCC2, and HMGA2 were differently expressed between human lung fibroblast (HLF) cells and cancer cells.ConclusionsHigh NM levels were revealed as a poor prognosis of LUAD. NMD regulates immune system through affecting aDCs and type II interferon response. The prognostic model with NM-related genes could be used to effectively evaluate the outcomes of patients.

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Molecular correlates and therapeutic targets in T cell-inflamed versus non-T cell-inflamed tumors across cancer types

Cited by 6 publications

References 51 publications

Pembrolizumab Plus Ipilimumab Following Anti-PD-1/L1 Failure in Melanoma

Pembrolizumab Plus Ipilimumab Following Anti-PD-1/L1 Failure in Melanoma

Dendritic Cells, the T-cell-inflamed Tumor Microenvironment, and Immunotherapy Treatment Response

Nitrogen Metabolism Disorder Accelerates Occurrence and Development of Lung Adenocarcinoma: A Bioinformatic Analysis and In Vitro Experiments

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