Tumor Mutation Burden and Differentially Mutated Genes Among Immune Phenotypes in Patients with Lung Adenocarcinoma

Hao Wang; Shanhao Chen; Die Meng; Chunyan Wu; Junjie Zhu; Minlin Jiang; Jing Ning; Shengyu Wu; Lijia Wu; Jingjie Li; Bin Chen; Sha Zhao; Wei Li; Jia Yu; Qiyu Fang; Jun Zhu; Wencheng Zhao; Yayi He; Caicun Zhou

doi:10.2147/OTT.S294993

Tumor Mutation Burden and Differentially Mutated Genes Among Immune Phenotypes in Patients with Lung Adenocarcinoma

Onco Targets Ther. 2021 May 4:14:2953-2965. doi: 10.2147/OTT.S294993. eCollection 2021.

Authors

Hao Wang^{1

2}, Shanhao Chen¹, Die Meng^{1

2}, Chunyan Wu³, Junjie Zhu⁴, Minlin Jiang^{1

2}, Jing Ning^{1

2}, Shengyu Wu^{1

2}, Lijia Wu⁵, Jingjie Li⁵, Bin Chen¹, Sha Zhao¹, Wei Li¹, Jia Yu^{1

2}, Qiyu Fang^{1

2}, Jun Zhu^{1

2}, Wencheng Zhao^{1

2}, Yayi He¹, Caicun Zhou¹

Affiliations

¹ Department of Medical Oncology, Shanghai Pulmonary Hospital, Shanghai, 200433, People's Republic of China.
² Medical School, Tongji University, Shanghai, 200433, People's Republic of China.
³ Pathology Department, Shanghai Pulmonary Hospital, Shanghai, 200433, People's Republic of China.
⁴ Surgery Department, Shanghai Pulmonary Hospital, Shanghai, 200433, People's Republic of China.
⁵ Genecast Biotechnology Co., Ltd, Wuxi City, Jiangsu, 214104, People's Republic of China.

Abstract

Introduction: Nowadays, immune checkpoint blockades (ICBs) have been extensively applied in non-small cell lung cancer (NSCLC) treatment. However, the outcome of anti-program death-1/program death ligand-1 (anti-PD-1/PD-L1) therapy is not satisfying in EGFR-mutant lung adenocarcinoma (LUAD) patients and its exact mechanisms have not been fully understood. Since tumor mutation burden (TMB) and tumor immune phenotype had been thought as potential predictors for efficacy of ICBs, we further studied the TMB and immune phenotype in LUAD patients to explore potential mechanisms for poor efficacy of ICBs in EGFR positive mutated patients and to find possible factors that could impact the tumor immune phenotype which might uncover some new therapeutic strategies or combination therapies.

Methods: We enrolled 223 LUAD patients who underwent surgery in our hospital. We evaluated TMB through targeted panel sequencing. The tumor immune phenotype, which could be divided into non-inflamed, intermediate and inflamed, was determined through immunohistochemistry using formalin-fixed paraffin-embedded samples. Enumeration data were analyzed by Chi-square test or Fisher exact test and shown as number (proportion). Logistic regression model was employed for univariate and multivariate analysis of the association between TMB levels and clinical characteristics.

Results: The median TMB level was 4.0445 mutations/Mb. Multivariate analysis showed the TMB level was significantly associated with age (P=0.026), gender (P=0.041) and EGFR mutation status (P=0.015), and in EGFR-mutant patients we found a lower proportion of patients with mutated KRAS and BRCA2. Furthermore, we found patients with or without metastatic lesions would have different immune phenotype (P=0.007). And the mutational frequencies of ALK, CDKN2A, MAP2K1, IDH2 and PTEN were significantly different among three immune phenotypes.

Conclusion: Low TMB level could be the reason for the poor efficacy of ICBs in patients having EGFR mutation. And mutational frequencies of KRAS and BRCA2 were lower in EGFR-mutant patients. Furthermore, ALK, CDKN2A, MAP2K1, IDH2 and PTEN might involve in the formation of immune phenotypes.

Keywords: EGFR mutation; immune checkpoint blockade; immune phenotype; lung adenocarcinoma; tumor mutation burden.

Grants and funding

This study was supported in part by a grant of young talents in Shanghai, National Natural Science Foundation of China (81802255), Young Talents in Shanghai (2019QNBJ), “Dream Tutor” Outstanding Young Talents Program (fkyq1901), Clinical Research Project of Shanghai Pulmonary Hospital (fk18005), Key Discipline in 2019 (oncology), Project of Shanghai Municipal Science and Technology Commission (Project of Municipal Science and Technology Commission), Scientific research project of Shanghai Pulmonary Hospital (fkcx1903), Shanghai Municipal Commission of Health and Family Planning (2017YQ050), Innovation Training Project of SITP of Tongji University, and key projects of leading talent (19411950300). Youth project of hospital management research fund of Shanghai Hospital Association (Q1902037).