Immune suppressive microenvironment in brain metastatic non-small cell lung cancer: comprehensive immune microenvironment profiling of brain metastases versus paired primary lung tumors (GASTO 1060)

Abstract

Lung cancer is one of the most common causes of brain metastases and is always associated with poor prognosis. We investigated the immunophenotypes of primary lung tumors and paired brain metastases, as well as immunophenotypes in the synchronous group (patients with brain metastases upon initial diagnosis) and metachronous group (patients developed brain metastases during the course of their disease). RNA sequencing of eighty-six samples from primary lung tumors and paired brain metastases of 43 patients was conducted to analyze the tumor immune microenvironment. Our data revealed that matched brain metastases compared with primary lung tumors exhibited reduced tumor infiltrating lymphocytes (TILs), a higher fraction of neutrophils infiltration, decreased scores of immune-related signatures, and a lower proportion of tumor microenvironment immune type I (high PD-L1/high CD8A) tumors. Additionally, we found a poor correlation of PD-L1 expression between paired brain metastases and primary lung tumors. In addition, gene set enrichment analysis (GSEA) showed that some gene sets associated with the immune response were enriched in the metachronous group, while other gene sets associated with differentiation and metastasis were enriched in the synchronous group in the primary lung tumors. Moreover, the tumor immune microenvironment between paired brain metastases and primary lung tumors displayed more differences in the metachronous group than in the synchronous group. Our work illustrates that brain metastatic tumors are more immunosuppressed than primary lung tumors, which may help guide immunotherapeutic strategies for NSCLC brain metastases.

Integrated Analyses of Multi-omic Data Derived from Paired Primary Lung Cancer and Brain Metastasis Reveals the Metabolic Vulnerability as a Novel Therapeutic Target

“…In addition, we performed WES, bulk RNAseq, proteomics and metabolomics of a newly generated cohort of patients presented at Sun Yat-sen University Cancer Center (SYSUCC) ( Fig. 1a ), among which RNAseq data of 24 patients was published in our previous study(Li et al, 2022). Overall, a total of 119 patients with paired primary lung cancer and BrM samples were included for genomic analysis; 56 patients were included for transcriptomic analysis; 16 patients were included for proteomic analysis (4 for proteomics and 12 for RPPA); and 4 patients were included for metabolomic analysis.…”

PD-(L)1 inhibitors plus bevacizumab and chemotherapy as first-line therapy in PD-L1-negative metastatic lung adenocarcinoma: a real-world data

“…We speculate that improvement of suppressive TIME by bevacizumab plays more obvious role in these subpopulation compared with that in their counterparts. It is reported that brain and liver metastasis lesions displayed an immunosuppressive state due to lack of tumor-infiltrating lymphocytes (TILs) [Li et al 2022 ; Deng et al 2023 ]. In addition, high VEGF level in the liver metastasis promotes tumor angiogenesis and leads to immune evasion by restricting the maturation of DCs and by reducing the expression of selectins, integrins, and adhesion molecules (Reck et al 2023 ).…”

Spatial and temporal heterogeneity of tumor immune microenvironment between primary tumor and brain metastases in NSCLC

“…We also noticed that previous literature has studied the relationship between the time interval of metastasis and the tumor microenvironment (including the expression of PD-L1) in paired NSCLC and brain metastases resected lesions. Most research results show that compared with metachronous metastasis, the tumor microenvironment of the primary tumor and brain metastasis tumor of synchronous brain metastasis is more consistent and less difference [ 28 , 43 – 45 ]. Only one literature reported different results [ 46 ].…”