No abstract

No abstract

Non‐small cell lung cancer (NSCLC) is one of the leading causes of death worldwide. Brain metastases are a common complication of a wide range of human malignancies, particularly lung adenocarcinoma (LUAD). Brain‐derived neurotrophic factor (BDNF), a member of the neurotrophin family, has been linked to several human malignancies and has been shown to promote LUAD tumorigenesis. However, its function in the tumour immune microenvironment (TIME) remains largely unexplored, especially in complex brain tissue environments. In this study, BDNF was found to be particularly increased in patients with advanced tumour stage, lymphatic metastasis, and distant metastasis, indicating a correlation with LUAD progression. We characterized the prognostic value of BDNF and defined BDNF as an unfavourable prognostic indicator through a common driver gene‐independent mechanism in LUAD. Furthermore, patients with increased BDNF levels in primary LUAD might have a higher risk of developing brain metastasis (BM), and central nervous system (CNS) metastasis showed an elevated expression of BDNF compared to their matched primary lesions. Additionally, we investigated the interaction between BDNF and infiltrating immune cells in both primary lesions and paired BM using multiplex immunostaining. The results showed that BDNF might drive an immunosuppressive tumour microenvironment (TME) by re‐education of tumour‐associated macrophages (TAMs) toward a pro‐tumorigenic M2 phenotype, particularly in BM. Our findings demonstrate that BDNF serves as an independent potential prognostic marker and correlates with BM in LUAD. As it is closely related to TAM polarization, BDNF may be a promising immune‐related biomarker and molecular target in patients with LUAD.

Background: Lung adenocarcinoma (LUAD) is a common subtype of non-small cell lung cancer with high morbidity and mortality rates and is usually detected at advanced stages because of the early onset of metastasis. Adenosine deaminase RNA-specific 1 (ADAR1) is an RNA editing enzyme that catalyzes the important physiological process of adenosine-to-inosine editing and has been shown to participate in the progression of LUAD. Increasing evidence has suggested that immune infiltration of the tumor immune microenvironment has prognostic value for most human solid organ malignancies; however, much is unknown about the functions of ADAR1. Methods:The expression of ADAR1 was analyzed in The Cancer Genome Atlas -LUAD database and validated in our LUAD cohort. To assess the prognostic value of ADAR1, Kaplan-Meier survival analyses and Cox regression analyses were carried out in LUAD cohorts. The association between ADAR1 and LUAD immune infiltrates via analyses of cell-type identification by estimating relative subsets of known RNA transcripts. Furthermore, multiplex immunohistochemistry was used to confirm the relationship between ADAR1 expression and immune cells in the present cohort of patients with LUAD.Results: ADAR1 was highly expressed in LUAD tissues and closely correlated with lymph node metastasis (LNM) (p < 0.01), advanced tumor stage (p < 0.05), and poor patient prognosis (p < 0.01), thus indicating that increased ADAR1 contributed to the progression of LUAD. LUAD with high ADAR1 expression can metastasize to lymph nodes that express more ADAR1 than the primary lesion.In addition, M0 macrophages and M2 macrophages increased and CD4 + T cells decreased in LUAD tissues with high ADAR1 expression. And the expression of ADAR1 in lymph node metastases was negatively correlated with the contents of CD4 + T cells (p = 0.0017) and M1 macrophages (p = 0.0037). Conclusion:The findings of our study suggested that ADAR1 may be useful in predicting prognosis and LNM in LUAD, and may serve as a promising immunerelated molecular target for LUAD patients.