EPHA mutation as a predictor of immunotherapeutic efficacy in lung adenocarcinoma

Bai, Hua; Duan, Jianchun; Li, Chengcheng; Xie, Wenzhuan; Fang, Wenfeng; Xu, Yu; Wang, Guoqiang; Wan, Rui; Sun, Jing; Xu, Jiachen; Wang, Xin; Fei, Kailun; Zhao, Zhengyi; Cai, Shangli; Zhang, Li; Wang, Jie; Wang, Zhijie

doi:10.1136/jitc-2020-001315

Cited by 27 publications

(19 citation statements)

References 36 publications

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“…In this regard, several predictors, including programmed cell death ligand 1 (PD-L1) expression, 5 tissue tumor mutational burden (TMB) 6 , 7 or blood TMB (bTMB), 8 Notch signaling, 9 the epoxide hydrolase (EPHA) gene family, 10 and tumor protein 53 (TP53) and kirsten rat sarcoma virus (KRAS) co-mutation, 11 are currently under investigation to identify patients that can benefit from ICIs. Meanwhile, several combination strategies including ICIs combined with chemotherapy have been developed to increase the response rate for ICIs.…”

Section: Introductionmentioning

confidence: 99%

TGFBR2 mutation predicts resistance to immune checkpoint inhibitors in patients with non-small cell lung cancer

Wang

et al. 2021

Ther Adv Med Oncol

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Background: Resistance or even hyper-progression to immune checkpoint inhibitors (ICIs) manifesting as accelerated disease progression or death has impeded the clinical use of ICIs. The transforming growth factor beta (TGFβ) receptor pathway has been identified in contributing to immune dysfunction, which might be associated with resistance to ICIs. We aimed to explore the role of TGFβ in the resistance to ICIs in non-small cell lung cancer (NSCLC) in this study. Methods: Public cohorts with patients treated with ICIs or chemotherapy including POPLAR/OAK ( n = 853), MSKCC ( n = 1662) and Van Allen ( n = 57) and TCGA ( n = 3210) cohorts were obtained and analyzed. Results: The expression of immune-checkpoint related genes, including programmed death-ligand 1 ( CD274), lymphocyte-activation gene 3 ( LAG3), T cell immunoreceptor with Ig and ITIM domains (TIGIT), cytotoxic T-lymphocyte-associated protein 4 ( CTLA-4), programmed cell death ligand 1 ( PDCD1), and programmed cell death 1 ligand 2 ( PDCD1LG2) were significantly upregulated in transforming growth factor beta TGFβ receptor 2 (TGFβR2)-mutated patients than those with wild-type TGFBR2 ( p < 0.05). In the POPLAR/OAK cohort, TGFBR2-mutated patients showed shorter progression-free survival (PFS) [ p = 0.004; hazard ratio (HR), 2.83; 95% confidence interval (CI), 1.34–6.00] and overall survival (OS) ( p = 0.0006; HR, 3.46; 95% CI, 1.63–7.35) than those with wild-type TGFBR2 when treated with ICIs but not chemotherapy. In the merged MSKCC and Van Allen cohorts, a similar result was observed that the OS was inferior in patients with mutated TGFBR2 compared with those with wild-type TGFBR2 ( p = 0.007; HR, 2.53; 95% CI, 1.25–5.12). The association between TGBFR2 mutation and survival remained significant in multivariable cox regression in both POPLAR/OAK cohort ( p = 0.02; HR, 2.53; 95% CI, 1.17–5.45) and merged cohort ( p = 0.008; HR, 2.63; 95% CI, 1.29–5.35). We further evaluated the association between TGFBR2 mutations and OS in multiple types of tumors. The association between TGFBR2 mutations and OS remained significant in NSCLC ( p = 0.02; HR, 2.47; 95% CI, 1.16–5.26), but not in other type of tumors. Conclusions: We identified that TGFBR2 mutation predicted the resistance to ICIs in NSCLCs. The clinical delivery of ICIs should be cautious in those patients.

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Section: Introductionmentioning

confidence: 99%

TGFBR2 mutation predicts resistance to immune checkpoint inhibitors in patients with non-small cell lung cancer

Wang

et al. 2021

Ther Adv Med Oncol

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“…found that ZFHX3 mutations were closely related to longer overall survival in NSCLC patients treated with ICBs and suggested that ZFHX3 mutations could be used as a novel predictive marker in guiding NSCLC ICB treatment ( 37 ). Recently, EPHA mutations were verified to be an independent classifier that could stratify patients with LUAD for ICB treatment ( 38 ). In this study, we demonstrated that RBM10 deficient population had higher TMB, and exhibited higher HLA and immune infiltration levels.…”

Section: Discussionmentioning

confidence: 99%

RBM10 Deficiency Is Associated With Increased Immune Activity in Lung Adenocarcinoma

Liu

Wang²,

Wang³

et al. 2021

Front. Oncol.

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IntroductionRBM10 is one of the frequently mutated genes in lung adenocarcinoma (LUAD). Previous studies have confirmed that RBM10 could suppress the disease progression and cell proliferation in LUAD, but its loss-of-function mutations are more frequent in early-stage disease and decrease with the advancement of the clinical stage. This is contradictory to its role of tumor suppressor. Here, we conducted a systematic analysis to elucidate whether there was other potential biological significance of RBM10 deficiency during the progression of LUAD.Materials and MethodsThe whole exome sequencing data of 39 tumor samples from early-stage LUADs (GGN cohort) and genomic and transcriptome data of the Cancer Genome Atlas (TCGA) LUAD cohort (TCGA_LUAD cohort) and a Chinese LUAD cohort (CHOICE_ADC cohort) were first obtained. Systematic bioinformatic analyses were then conducted to determine gene expression signature, immune infiltration levels and predicted immunotherapy response. Immunohistochemistry (IHC) was also conducted to validate the result of immune infiltration.ResultsThe mutation rate of RBM10 was significantly higher in the GGN cohort than that in the TCGA_LUAD and CHOICE_ADC cohorts. In both TCGA_LUAD and CHOICE_ADC cohorts, multiple immune related pathways were markedly enriched in RBM10 deficient group. Further analyses showed that tumors with RBM10 mutations displayed higher TMB, and LUADs with RBM10 deficiency also showed higher HLA expression levels, including many HLA class I and II molecules. Additionally, many immune cells, including myeloid dendritic cells, macrophages, neutrophils and CD8+T cells, showed higher infiltration levels in LUADs with RBM10 deficiency. Finally, some immune checkpoint molecules, such as PD-L1 and TIM-3, were highly expressed in RBM10 deficient population and the predicted immunotherapy response was calculated through TIDE algorithm, showing that IFNG expression, MSI score and CD8 expression were higher in RBM10 deficient group, while MDSC and M2 macrophage were lower in RBM10 deficient group.ConclusionOur study demonstrates that RBM10 deficient LUADs show higher HLA expression and immune cell infiltration, and some immune checkpoint molecules are also highly expressed. In brief, RBM10 deficiency could enhance anti-tumor immunity in LUAD.

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“…For example, immune checkpoint inhibitors (ICIs) have been approved as the first-line treatment for advanced-stage lung squamous cell carcinoma with PD-L1 expression >1% (7)(8)(9). However, the heterogeneity of the tumor microenvironment brings confusing treatment response among individual patients (10). It is documented that some patients with high PD-L1 expression do not respond to ICIs while some patients with low PD-L1 expression obtain benefits from ICI treatment.…”

Section: Introductionmentioning

confidence: 99%

Identification of Immune Subtypes of Lung Squamous Cell Carcinoma by Integrative Genome-Scale Analysis

Yin

Zhang

et al. 2022

Front. Oncol.

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BackgroundCharacterization of the tumor microenvironment is helpful to understand the tumor immune environment of lung cancer and help predict the prognosis.MethodsFirst, immune subtypes were identified by consensus subtype among lung squamous carcinoma (LUSC) patients. Immune cell infiltration was evaluated by CIBERSORT and ESTIMATE analyses. Then, based on differentially expressed genes (DEGs) identified, a risk score model was constructed. Finally, gene FPR1 was validated by using YTMLC-90.FindingsLUSC samples were divided into four heterogeneous immune subtypes, with significantly different prognoses with subtype 4 having the poorest overall survival (OS). The immune infiltration score showed that subtype 4 was characterized as immune enriched and fibrotic, while subtype 3 was tumor enriched. DEG analysis showed that upregulated genes in subtype 4 were enriched of neutrophil and exhausted T cell-related biological processes. Based on a univariate Cox regression model, prognostic 7 immune-related genes were combined to construct a risk score model and able to predict OS rates in the validation datasets. Wound healing and transwell assay were conducted to evaluate the invasion property after activating the gene FPR1.InterpretationThe analysis of tumor immune microenvironments among LUSC subtypes may provide new insights into the strategy of immunotherapy.

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EPHA mutation as a predictor of immunotherapeutic efficacy in lung adenocarcinoma

Cited by 27 publications

References 36 publications

TGFBR2 mutation predicts resistance to immune checkpoint inhibitors in patients with non-small cell lung cancer

TGFBR2 mutation predicts resistance to immune checkpoint inhibitors in patients with non-small cell lung cancer

RBM10 Deficiency Is Associated With Increased Immune Activity in Lung Adenocarcinoma

Identification of Immune Subtypes of Lung Squamous Cell Carcinoma by Integrative Genome-Scale Analysis

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