scholarly journals Differences in Immunological Landscape between EGFR-Mutated and Wild-Type Lung Adenocarcinoma

2021 ◽  
Vol 2021 ◽  
pp. 1-8
Author(s):  
Jia-Wei Luo ◽  
Yan-Hua Guo ◽  
Feng-Ying Wu ◽  
Xue-Fei Li ◽  
Xue-Cheng Sun ◽  
...  
Keyword(s):  
Tumor Microenvironment ◽  
Lung Adenocarcinoma ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Immune Cell ◽  
Checkpoint Inhibitors ◽  
Disease Free Survival ◽  
Egfr Mutations ◽  
Wild Type ◽  
Egfr Mutant

Recent clinical trials of lung adenocarcinoma with immune checkpoint inhibitors revealed that lung adenocarcinoma patients with EGFR mutations have a poor response to immunotherapy. However, the mechanisms have not been addressed. We performed immunohistochemistry analyses of resected lung adenocarcinoma tissues with and without EGFR mutations to investigate and compare the characteristics of the tumor microenvironment (TME). We retrospectively enrolled a total of 323 lung adenocarcinoma patients (164 had EGFR mutations), and their corresponding tissue samples were analyzed by the EGFR mutation test and immunohistochemistry. We selected the markers of the immune checkpoint molecule (PD1, PD-L1, and LAG-3) and immune cell (CD3, CD4, CD8, and Foxp3) as markers of the tumor microenvironment. Our results revealed that patients had a distinct tumor microenvironment between EGFR-mutant and wild-type lung adenocarcinomas; the expression of CD3, CD4, PD-L1, and Foxp3 in EGFR-mutant tumors was significantly higher than that in wild-type tumors, while the expression of LAG3 and PD-1 showed a positive correlation with EGFR-wild-type tumors. In survival analysis, EGFR-wild-type patients had longer disease-free survival (DFS) than EGFR-mutant patients ( P = 0.0065 ). Our research demonstrates significant differences in tumor microenvironment composition between EGFR-mutant and wild-type patients. Our findings provide novel evidence that contributes to understanding the mechanism underlying the poor efficacy of immune checkpoint inhibitors.

scholarly journals Role of the dynamic tumor microenvironment in controversies regarding immune checkpoint inhibitors for the treatment of non-small cell lung cancer (NSCLC) with EGFR mutations

2019 ◽  
Vol 18 (1) ◽  
Author(s):  
Anqi Lin ◽  
Ting Wei ◽  
Hui Meng ◽  
Peng Luo ◽  
Jian Zhang
Keyword(s):  
Lung Cancer ◽  
Tumor Microenvironment ◽  
Small Cell Lung Cancer ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Small Cell ◽  
Egfr Mutations ◽  
Small Cell Lung ◽  
Egfr Mutant

Abstract Immunotherapy has been incorporated into the first- and second-line treatment strategies for non-small cell lung cancer (NSCLC), profoundly ushering in a new treatment landscape. However, both adaptive signaling and oncogenic (epidermal growth factor receptor (EGFR)-driven) signaling may induce PD-L1 upregulation in NSCLC. Nevertheless, the superiority of immune checkpoint inhibitors (ICIs) in advanced EGFR-mutant NSCLC is only moderate. ICIs appear to be well tolerated, but clinical activity for some advanced EGFR-mutant NSCLC patients has only been observed in a small proportion of trials. Hence, there are still several open questions about PD-L1 axis inhibitors in patients with NSCLC whose tumors harbor EGFR mutations, such as the effect of EGFR tyrosine kinase inhibitors (TKIs) or EGFR mutations in the tumor microenvironment (TME). Finding the answers to these questions requires ongoing trials and preclinical studies to identify the mechanisms explaining this possible increased susceptibility and to identify prognostic molecular and clinical markers that may predict benefits with PD-1 axis inhibition in this specific NSCLC subpopulation. The presence of multiple mechanisms, including dynamic immune TME profiles, changes in PD-L1 expression and low tumor mutational burdens, may explain the conflicting data regarding the correlation between PD-L1 axis inhibitors and EGFR mutation status. We conducted a review of this currently controversial topic in an attempt to aid in the decision-making process.

scholarly journals Application of immune checkpoint inhibitors in EGFR-mutant non-small-cell lung cancer: from bed to bench

2020 ◽  
Vol 12 ◽  
pp. 175883592093033
Author(s):  
Rui Jin ◽  
Jing Zhao ◽  
Lexin Xia ◽  
Qin Li ◽  
Wen Li ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Small Cell Lung Cancer ◽  
Targeted Therapies ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Small Cell ◽  
Egfr Mutations ◽  
Small Cell Lung ◽  
Egfr Mutant

Targeted therapies are efficient in the context of oncogenic driver mutations. Epidermal growth factor receptor (EGFR)-mutant lung cancers represent a distinct subset of non-small-cell lung cancer (NSCLC) with marked sensitivity to EGFR tyrosine kinase inhibitors (TKIs). Despite the high response rate to EGFR TKIs in EGFR-mutant lung cancer, resistance and tumor recurrence are unavoidable. Therapeutic options are restricted in patients after exhaustion of targeted therapies. Immune checkpoint inhibitors (ICIs) represent a novel therapeutic option for advanced NSCLC with significant overall survival benefit in registration trials. No superiority in terms of long-term survival was observed in the EGFR mutation subgroup when ICIs were given as monotherapy in second-line treatment in earlier studies. Thus, the appropriate application of ICIs to patients harboring EGFR mutations remains an important field of ongoing research. Here, we discuss different immune checkpoint blockade strategies, including ICIs alone and in combination with TKIs, chemotherapy, radiation, and antiangiogenic agents in EGFR-mutant NSCLC as first-line and subsequent treatments. We also summarize the evidence concerning the heterogeneous molecular features and immune signatures of EGFR mutations and their associations with ICI therapy outcomes. This study was performed to improve our understanding of the optimal mode of immune-based treatment approaches in EGFR-mutant NSCLC.

Combination of biomarker and clinicopathologic characters to circle out beneficiaries through second-line immunotherapy: A meta analyse.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. e14535-e14535
Author(s):  
C Zhang ◽  
Wenzhao Zhong ◽  
Zhong yi Dong ◽  
Yi-Long Wu
Keyword(s):  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Smoking Status ◽  
Single Agent ◽  
Egfr Mutations ◽  
Second Line ◽  
Wild Type ◽  
Second Line Therapy ◽  
Line Therapy

e14535 Background: Programmed cell death ligand 1 (PD-L1) expression had been proposed as predictive biomarker to immune-checkpoint inhibitors. Yet treatment responses are not always consistent with this single agent in the second-line therapy of non-small cell lung cancer (NSCLC). Whether combination of PD-L1 and clinicopathologic characters could circle out optimal beneficiaries are still unknown. Methods: We performed a meta-analysis of randomized control trials that compared immune-checkpoint inhibitors against chemotherapy in second-line therapy. Data including smoking status, EGFR status, KRAS status and histology were extracted as subgroup analyse to estimate the potential predictor of efficacy for anti PD-1/L1. Results: Five clinical trials that compared immune-checkpoint inhibitors against chemotherapy for second-line therapy were included. Both PD-L1 positive (HR = 0.64, 95%CI = 0.56-0.73, P < 0.00001) and PD-L1 negative (HR = 0.88, 95%CI = 0.78-1.00, P = 0.05) favored anti PD-1/L1. Subgroup analyse indicated that adenocarcinoma (ADC) as well as squamous cell carcinoma (SCC) preferred anti PD-1/L1. Never smokers may not benefit from anti PD-1/L1 but current/ever smokers did (HR = 0.70, 95%CI = 0.63-0.79, P < 0.00001). Patients with EGFR mutation could not gain benefit from anti PD-1/L1 while the EGFR wild type could (HR = 0.67, 95%CI = 0.60-0.76, P < 0.00001). Both KRAS mutation (HR = 0.60, 95%CI = 0.39-0.92, P = 0.02) and wild type/unknown (HR = 0.81, 95%CI = 0.67-0.97, P = 0.02) were apt to anti PD-1/L1. Conclusions: Regardless of PD-L1 status, immune-checkpoint inhibitors could achieve better efficacy than chemotherapy in second-line therapy. Current/ever smokers without EGFR mutations may benefit more from anti PD-1/L1. Combination of PD-L1 and strongly relevant clinicopathologic characters should be considered to tailor optimal patients for anti PD-1/L1.

Immune checkpoint inhibitors combined with chemotherapy/radiotherapy, for EGFR wild-type lung cancer: Efficacy in real-world study.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. e15117-e15117
Author(s):  
Jifeng Feng ◽  
Yue Shi
Keyword(s):  
Lung Cancer ◽  
Lung Adenocarcinoma ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Multivariable Analysis ◽  
Cox Proportional Hazards Model ◽  
Combined Chemotherapy ◽  
Line Treatment ◽  
Wild Type

e15117 Background: The role of immune checkpoint inhibitors (anti-PD-1 antibody, ICI) combined with chemotherapy/radiotherapy for EGFR wild-type lung cancer is controversial, especially in 2nd-line or later treatment. The purpose of this study was to investigate the possible beneficial factors for immunotherapy for EGFR wild-type lung cancer. Methods: A total of 279 patients with EGFR wild-type lung cancer who received ICI were retrospectively analyzed, including 138 adenocarcinoma, 76 squamous carcinoma and 31 SCLC patients. Beneficial factors were determined by multivariable Cox proportional hazards model for PFS. PFS and ORR were compared between different therapies. Results: The specific results are shown in table. In multivariable analysis, ICI combined radiotherapy (P = 0.018; HR, 0.152(95% CI: 0.032, 0.727)) was identified as an effective independent factor for EGFR wild-type lung adenocarcinoma. PFS in patients who received ICI combined radiotherapy was significantly longer than that in those who received ICI monotherapy ((p = 0.032; not reached vs. 9.6 m (95% CI: 5.627, 13.640))). Among lung adenocarcinoma patients who received ICI as 2nd-line treatment, patients treated by ICI combined chemotherapy showed more benefit than those treated by ICI monotherapy (P = 0.003; HR, 0.012(95% CI: 0.001, 0.213)).ICI combined chemotherapy can significantly prolong PFS compared with those treated by ICI monotherapy (p = 0.015; 14.3 m [95% CI: 8.711, 19.822] vs. 1.1 m (95% CI: 0.25, 1.883)) in the 2nd-line treatment. However, ORR showed no significant different between ICI monotherapy and ICI combined chemotherapy(P = 0.626). Conclusions: ICI combined with radiotherapy showed better result than those who didn’t receive radiotherapy for EGFR wild-type lung adenocarcinoma. The addition of chemotherapy to ICI for the 2nd-line treatment in EGFR wild-type lung adenocarcinoma patients seems get more clinical benefit than ICI monotherapy. [Table: see text]

scholarly journals Diffuse Cystic Metastases in the Lung after Nivolumab Treatment in a Patient with Non-Small Cell Lung Cancer: A Case Report

2021 ◽  
pp. 34-38
Author(s):  
Satoshi Muto ◽  
Yuki Ozaki ◽  
Takuya Inoue ◽  
Naoyuki Okabe ◽  
Yuki Matsumura ◽  
...  
Keyword(s):  
Lung Adenocarcinoma ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Lung Metastases ◽  
Sialyl Lewis X ◽  
Ground Glass ◽  
Cystic Lesions ◽  
Positron Emission ◽  
Ground Glass Nodules

Although diffuse cysts in the lung can be found in many diseases, they are uncommon in metastatic lung adenocarcinoma. They are even more unusual after the administration of immune checkpoint inhibitors. A case of lung adenocarcinoma that developed diffuse cysts in the lungs during treatment with nivolumab is reported. The patient was a 60-year-old woman with postoperative recurrent lung adenocarcinoma in mediastinal lymph nodes and pleural dissemination. After first-line treatment with cisplatin, pemetrexed, and bevacizumab, computed tomography (CT) showed disease progression. Treatment was then switched to nivolumab. After 5 courses of nivolumab, CT showed multiple ground-glass nodules in her lungs. After 4 more courses of nivolumab, the ground-glass nodules increased in size, and cystic air spaces appeared in their centers. The patient did not have any symptoms. Laboratory tests showed no evidence of infection or nivolumab-induced pneumonitis. Sialyl Lewis X-i antigen increased, and positron emission tomography showed abnormal uptake of 18F-fluorodeoxyglucose in these lesions. Considering this evidence, the cystic lesions were diagnosed as multiple lung metastases. Various differential diagnoses should be considered when diffuse cystic lesions are found in the lungs after the administration of immune checkpoint inhibitors.

RNF43 mutations to predict survival from treatment with immune checkpoint inhibitors and are associated with a high tumor mutation burden in bladder cancer.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. e16528-e16528
Author(s):  
Liping Li ◽  
Mengmei Yang ◽  
Mengli Huang
Keyword(s):  
Bladder Cancer ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Negative Regulator ◽  
Wilcoxon Test ◽  
Wild Type ◽  
Tumor Mutation Burden ◽  
Mutation Burden ◽  
The Impact

e16528 Background: Immune checkpoint inhibitors (ICIs) targeting PD-1/L1 have been approved as first-line treatment for cisplatin-ineligible patients and as second-line therapy for patients with metastatic urothelial carcinoma of the bladder. Biomarkers can help select patients who are more likely to response to ICIs. RNF43 is an E3 ubiquitin ligase that acts as a negative regulator of Wnt/β-catenin signaling pathway. In colorectal cancer (CRC) patients treated with immune checkpoint inhibitors (ICIs), RNF43 mutations predicted longer overall survival (OS). The impact of RNF43 mutations on the efficiency of ICIs in bladder cancer(BLC) remains to be explored. Methods: We downloaded the mutation and clinical data of 211 BLC patients treated with ICIs from the immunotherapeutic cohort published by Samstein et al. (2019). OS analyses were conducted using Kaplan-Meier curves and log-rank tests. Wilcoxon test was used for the comparison of TMB. We also downloaded a TCGA cohort for prognostic analysis. The correlations between RNF43 and immune infiltrates were analyzed in the TIMER2.0 database. Statistical significance was set at p = 0.05. Results: RNF43 mutations were identified in 4.3%(9/211) and 3%(13/438) BLC patients in the immunotherapeutic and TCGA cohort, respectively. In the immunotherapeutic cohort, patients with RNF43 mutations had significantly longer OS (25 months vs 8 months; p = 0.015) and higher tumor mutation burden(TMB, 42.3 vs 7.9; p = 3.15E-06) than RNF43-wild-type patients. Different from this, no significant difference was found in OS between RNF43-mutant and RNF43-wild-type BLC patients with standard treatment in the TCGA cohort (p = 0.696). These results indicated that RNF43 was not a prognostic factor but a predictive biomarker of survival in BLC treated with ICIs. No difference was observed in subsets of immune cells between RNF43-mutant and the RNF43-wide-type BLC patients, including neutrophils, macrophages, CD8+ T cells, Tregs, B cells and NK cells. Conclusions: RNF43 mutations may be a predictor of survival benefit from ICIs in bladder cancer and correlated with higher TMB. Further studies in other ICI-treated cohorts are needed to confirm these results.

Impact of Use of Antibiotics on Response to Immune Checkpoint Inhibitors and Tumor Microenvironment

2021 ◽  
Vol Publish Ahead of Print ◽  
Author(s):  
Uqba Khan ◽  
Kaylee Ho ◽  
Eun Kyeong Hwang ◽  
Cristian Peña ◽  
Julianna Brouwer ◽  
...  
Keyword(s):  
Tumor Microenvironment ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors
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