Genetic Intratumor Heterogeneity Remodels the Immune Microenvironment and Induces Immune Evasion in Brain Metastasis of Lung Cancer

Authors

Xin Wang
Hua Bai
Jiyang Zhang
Zhijie Wang
Jianchun Duan
Hongqing Cai
Zheng Cao
Qingtang Lin
Xiaosheng Ding
Yiting Sun
Wei Zhang
Xiaoya Xu
Hao Chen
Dadong Zhang
Xiaoli Feng
Jinghai Wan
Jianjun Zhang
Jie He
Jie Wang

Publication Date

2-1-2024

Journal

Journal of Thoracic Oncology

DOI

10.1016/j.jtho.2023.09.276

PMID

37717855

Abstract

Introduction: Brain metastasis, with the highest incidence in patients with lung cancer, significantly worsens prognosis and poses challenges to clinical management. To date, how brain metastasis evades immune elimination remains unknown.

Methods: Whole-exome sequencing and RNA sequencing were performed on 30 matched brain metastasis, primary lung adenocarcinoma, and normal tissues. Data from The Cancer Genome Atlas primary lung adenocarcinoma cohort, including multiplex immunofluorescence, were used to support the findings of bioinformatics analysis.

Results: Our study highlights the key role of intratumor heterogeneity of genomic alterations in the metastasis process, mainly caused by homologous recombination deficiency or other somatic copy number alteration-associated mutation mechanisms, leading to increased genomic instability and genomic complexity. We further proposed a selection model of brain metastatic evolution in which intratumor heterogeneity drives immune remodeling, leading to immune escape through different mechanisms under local immune pressure.

Conclusions: Our findings provide novel insights into the metastatic process and immune escape mechanisms of brain metastasis and pave the way for precise immunotherapeutic strategies for patients with lung cancer with brain metastasis.

Keywords

Humans, Lung Neoplasms, Immune Evasion, Mutation, Adenocarcinoma of Lung, Brain Neoplasms, Genetic Heterogeneity, Tumor Microenvironment, Brain metastasis, Immune editing, Intra-tumor heterogeneity, Patient-paired samples, Precise immunotherapy

Published Open-Access

yes

Recommended Citation

Wang, Xin; Bai, Hua; Zhang, Jiyang; et al., "Genetic Intratumor Heterogeneity Remodels the Immune Microenvironment and Induces Immune Evasion in Brain Metastasis of Lung Cancer" (2024). Faculty, Staff and Student Publications. 5095.
https://digitalcommons.library.tmc.edu/uthgsbs_docs/5095