KEAP1-driven co-mutations in lung adenocarcinoma unresponsive to immunotherapy despite high tumor mutational burden

Marinelli, Daniele; Mazzotta, Marco; Scalera, Stefano; Terrenato, Irene; Sperati, Francesca; D’Ambrosio, Luigi; Pallocca, Matteo; Corleone, Giacomo; Krasniqi, Eriseld; Pizzuti, Laura; Barba, Maddalena; Carpano, Silvia; Vici, Patrizia; Filetti, Marco; Giusti, Raffaele; Vecchione, Andrea; Occhipinti, Mario; Gelibter, Alain; Botticelli, Andrea; Nicola, Francesca De; Ciuffreda, Ludovica; Goeman, Frauke; Gallo, Enzo; Visca, Paolo; Pescarmona, Edoardo; Fanciulli, Maurizio; Maria, Ruggero De; Marchetti, Paolo; Ciliberto, Gennaro; Maugeri‐Saccà, Marcello

doi:10.1016/j.annonc.2020.08.2105

Cited by 176 publications

(143 citation statements)

References 57 publications

Supporting

Mentioning

122

Contrasting

Order By: Relevance

“…For example, the TIME has been shown to have less immune-cell infiltration in STK11-mutation patients who have a worse prognosis after immunotherapy (27). A similar phenomenon was also observed in patients with KEAP1 mutations, despite a high TMB level (28). Our data shows that the D scores of BRAF, ERBB2, MET, or KRAS were very similar, suggesting that they may have similar TIMEs in some ways.…”

Section: Discussionsupporting

confidence: 76%

Exploration of the Tumor-Suppressive Immune Microenvironment by Integrated Analysis in EGFR-Mutant Lung Adenocarcinoma

Pang

Wang

et al. 2021

Front. Oncol.

View full text Add to dashboard Cite

BackgroundClinical evidence has shown that few non-small cell lung cancer (NSCLC) patients with epidermal growth factor receptor (EGFR) mutations can benefit from immunotherapy. The tumor immune microenvironment (TIME) is a significant factor affecting the efficacy of immunotherapy. However, the TIME transformational process in EGFR-mutation patients is unknown.MethodsThe mRNA expression and mutation data and lung adenocarcinoma (LUAD) clinical data were obtained from The Cancer Genome Atlas (TCGA) database. Profiles describing the immune landscape of patients with EGFR mutations were characterized by differences in tumor mutation burden (TMB), ESTIMATE, CIBERSORT, and microenvironment cell populations-counter (MCP-counter).ResultsIn total, the TCGA data for 585 patients were analyzed. Among these patients, 98 had EGFR mutations. The TMB was lower in the EGFR group (3.94 mut/Mb) than in the KRAS mutation group (6.09 mut/Mb, P < 0.001) and the entire LUAD (6.58 mut/Mb, P < 0.001). The EGFR group had a lower population of activated immune cells and an even higher score of immunosuppressive cells. A further inter-group comparison showed that differences in the TMB and tumor-infiltrating lymphocytes were only found between patients with oncogenic mutations and unknown mutation. Meanwhile, there were more myeloid dendritic cells (DCs) in EGFR 19del than in L858R-mutation patients and in common mutation patents than in uncommon mutation patients (P < 0.05). Additionally, we established a D score, where D = MCP-counter score for cytotoxic T lymphocytes (CTLs)/MCP-counter score for myeloid DCs. Further analysis revealed that lower D scores indicated immune suppression and were negatively related to several immunotherapy biomarkers.ConclusionsThe TIME of EGFR mutant NSCLC was immunosuppressive. Myeloid DCs gradually increased in EGFR 19del, L858R, and uncommon mutations. The potential role of CTLs and DCs in the TIME of patients requires further investigation.

show abstract

Section: Discussionsupporting

confidence: 76%

Exploration of the Tumor-Suppressive Immune Microenvironment by Integrated Analysis in EGFR-Mutant Lung Adenocarcinoma

Pang

Wang

et al. 2021

Front. Oncol.

View full text Add to dashboard Cite

show abstract

“…More importantly, some gene mutations affected the prognosis and treatment effects of cancer patients. Recent studies have shown that gene mutations were closely related to the effect of tumor immunotherapy (63)(64)(65)(66). In order to gain insight into the possible mechanism of this risk model for predicting the prognosis of patients with early stage LUSC, we studied the relationship between the risk score and the top ten genes with mutation frequency.…”

Section: Discussionmentioning

confidence: 99%

A Novel Immune-Related Seventeen-Gene Signature for Predicting Early Stage Lung Squamous Cell Carcinoma Prognosis

Fan

Liu

et al. 2021

Front. Immunol.

View full text Add to dashboard Cite

With the increasingly early stage lung squamous cell carcinoma (LUSC) being discovered, there is an urgent need for a comprehensive analysis of the prognostic characteristics of early stage LUSC. Here, we developed an immune-related gene signature for outcome prediction of early stage LUSC based on three independent cohorts. Differentially expressed genes (DEGs) were identified using CIBERSORT and ESTMATE algorithm. Then, a 17-immune-related gene (RPRM, APOH, SSX1, MSGN1, HPR, ISM2, FGA, LBP, HAS1, CSF2, RETN, CCL2, CCL21, MMP19, PTGIS, F13A1, C1QTNF1) signature was identified using univariate Cox regression, LASSO regression and stepwise multivariable Cox analysis based on the verified DEGs from 401 cases in The Cancer Genome Atlas (TCGA) database. Subsequently, a cohort of GSE74777 containing 107 cases downloaded from Gene Expression Omnibus (GEO) database and an independent data set consisting of 36 frozen tissues collected from National Cancer Center were used to validate the predictive value of the signature. Seventeen immune-related genes were identified from TCGA cohort, which were further used to establish a classification system to construct cases into high- and low-risk groups in terms of overall survival. This classifier was still an independent prognostic factor in multivariate analysis. In addition, another two independent cohorts and different clinical subgroups validated the significant predictive value of the signature. Further mechanism research found early stage LUSC patients with high risk had special immune cell infiltration characteristics and gene mutation profiles. In conclusion, we characterized the tumor microenvironment and established a highly predictive model for evaluating the prognosis of early stage LUSC, which may provide a lead for effective immunotherapeutic options tailored for each subtype.

show abstract

“…Additional positive predictive biomarkers include CD274 (PD‐L1) gene amplification, which has shown some evidence as a predictor to PD‐L1/PD‐1 therapy response in solid tumors [5]. Importantly, potential resistance biomarkers ( STK11 and KEAP1 alterations) for patients treated with immune checkpoint inhibitors (ICPIs) have emerged in several tumor types [6, 7]. Last, we were interested in investigating the APOBEC mutational signature in UC because of its known association with increased survival of patients with bladder cancer [8].…”

Section: Introductionmentioning

confidence: 99%

Clinicopathologic and Genomic Characterization of PD-L1 Positive Urothelial Carcinomas

Huang¹,

Haberberger²,

Harries³

et al. 2021

The Oncologist

View full text Add to dashboard Cite

Introduction. Pembrolizumab was approved with an accompanying companion diagnostic (CDx) assay (PD-L1 DAKO 22C3) for urothelial carcinoma (UC). In this study, we further characterize the clinicopathologic and genomic features of UC that are PD-L1 positive. Materials and Methods. The cohort of this study consisted of a total of 528 consecutive UC patients with PD-L1 IHC and comprehensive genomic profiling (CGP). All PD-L1 IHC testing was performed using the DAKO 22C3 CDx assay for UC. PD-L1 positivity was determined at a combined positive score (CPS) ≥ 10. Results. 44.5% of 528 consecutive UC patients were PD-L1 positive. A lower PD-L1 positivity rate was detected in primary (42.3%, 148/350) vs metastatic sites (48.9%, 87/178). PD-L1 positivity was dependent on the location of the metastatic sites with PD-L1 positivity rate. CGP revealed PD

show abstract

KEAP1-driven co-mutations in lung adenocarcinoma unresponsive to immunotherapy despite high tumor mutational burden

Cited by 176 publications

References 57 publications

Exploration of the Tumor-Suppressive Immune Microenvironment by Integrated Analysis in EGFR-Mutant Lung Adenocarcinoma

Exploration of the Tumor-Suppressive Immune Microenvironment by Integrated Analysis in EGFR-Mutant Lung Adenocarcinoma

A Novel Immune-Related Seventeen-Gene Signature for Predicting Early Stage Lung Squamous Cell Carcinoma Prognosis

Clinicopathologic and Genomic Characterization of PD-L1 Positive Urothelial Carcinomas

Contact Info

Product

Resources

About