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Although epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs), especially third-generation TKIs, have significantly improved the progression-free survival and overall survival of non-small cell lung cancer (NSCLC) patients with EGFR mutation, TKI resistance is inevitable for most patients. Over the past few years, immune checkpoint inhibitors (ICIs) have significantly improved the survival for EGFR-wild type NSCLC patients. However, no significantly improved benefits were observed with ICI monotherapy in EGFR-mutated patients. EGFR-mutated NSCLC shows more heterogeneity in tumor mutational burden (TMB), programmed cell death-ligand 1 (PD-L1), and immune microenvironment characteristics. Whether ICIs are suitable for EGFR-mutated NSCLC patients remains to be elucidated. In this review, we summarized clinical trials of ICIs or combined therapy in EGFR-mutated NSCLC patients. We further discussed the factors determining the efficacy of ICIs in EGFR-mutated NSCLC patients, the mutation subtypes and microenvironment characteristics of potential responders. More importantly, we provided insights into areas worth further investigation in the future., (© 2024 The Author(s). Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.)

Background: In China, lung cancer remains the cancer with the highest incidence and mortality rate. Among early-stage lung adenocarcinomas (LUAD), the micropapillary (MPP) component is prevalent and typically exhibits high aggressiveness, significantly correlating with early metastasis, lymphatic infiltration, and reduced five-year survival rates. Therefore, the study is to explore the similarities and differences between MPP and non-micropapillary (non-MPP) components in malignant pulmonary nodules characterized by GGOs in early-stage LUAD, identify unique mutational features of the MPP component and analyze the relationship between the ZNF469 gene, a member of the zinc-finger protein family, and the prognosis of early-stage LUAD, as well as its correlation with immune infiltration., Methods: A total of 31 malignant pulmonary nodules of LUAD were collected and dissected into paired MPP and non-MPP components using microdissection. Whole-exome sequencing (WES) was performed on the components of early-stage malignant pulmonary nodules. Mutational signatures analysis was conducted using R packages such as maftools, Nonnegative Matrix Factorization (NMF), and Sigminer to unveil the genomic mutational characteristics unique to MPP components in invasive LUAD compared to other tumor tissues. Furthermore, we explored the expression of the ZNF469 gene in LUAD using The Cancer Genome Atlas (TCGA) database to investigate its potential association with the prognosis. We also investigated gene interaction networks and signaling pathways related to ZNF469 in LUAD using the GeneMANIA database and conducted Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis. Lastly, we analyzed the correlation between ZNF469 gene expression and levels of immune cell infiltration in LUAD using the TIMER and TISIDB databases., Results: MPP components exhibited a higher number of genomic variations, particularly the 13th COSMIC (Catalogue of Somatic Mutations in Cancer) mutational signature characterized by the activity of the cytidine deaminase APOBEC family, which was unique to MPP components compared to non-MPP components in tumor tissues. This suggests the potential involvement of APOBEC in the progression of MPP components in early-stage LUAD. Additionally, MPP samples with high similarity to APOBEC signature displayed a higher tumor mutational burden (TMB), indicating that these patients may be more likely to benefit from immunotherapy. The expression of ZNF469 was significantly upregulated in LUAD compared to normal tissue, and was associated with poor prognosis in LUAD patients (P<0.05). Gene interaction network analysis and GO/KEGG enrichment analysis revealed that COL6A1, COL1A1, COL1A2, TGFB2, MMP2, COL8A2 and C2CD4C interacted with ZNF469 and were mainly involved in encoding collagen proteins and participating in the constitution of extracellular matrix. ZNF469 expression was positively correlated with immune cell infiltration in LUAD (P<0.05)., Conclusions: The study has unveiled distinctive mutational signatures in the MPP components of early-stage invasive LUAD in the Asian population. Furthermore, we have identified that the elevated expression of mutated ZNF469 impacts the prognosis and immune infiltration in LUAD, suggesting its potential as a diagnostic and prognostic biomarker in LUAD.

Introduction: The nuclear factor kB (NF-κB) pathway emerges as a critical regulator of immune responses and is often dysregulated in human cancers. It consists of a family of transcription factors involved in many biological responses. Activated NF-κB subunits results in the nuclear translocation and activation of transcription, and the NF-κB pathway is known to influence the transcription of many genes. Noncanonical NF-κB and its components have been shown to have effects, usually protumorigenic, in many different cancer types. Besides, NF-κB signaling had diverse and complicated roles in cancer with studies that NF-κB could both contribute to tumor promotion and suppression of oncogenesis relying on the cellular context. RelB, a member of noncanonical NF-κB was abnormally regulated in most cancer types, however the molecular features and clinical signature of RelB expression, as well as its role in cancer immunity in human pan-cancer remains to be elucidated. Methods: We used the open databases to explore RelB expression, clinical features and the association with tumor-infiltration cells in human pan-cancer. In this study, we investigated the aberration expression and prognostic significance of RelB, and the correlation with clinicopathological characters and immune cells infiltration in various cancers. The Cancer Genome Atlas (TCGA) and Genotype-Tissue Expression (GTEx) databases were used to analyze the mRNA expression level in different cancer types. Kaplan-Meier analysis and Cox regression were used to explore the prognostic significance of RelB in human pan-cancer. Then we took advantage of the TCGA database to analyze the relationship between RelB expression and DNA methylation, the infiltration of immune cells, immune checkpoint genes, tumor mutation burden (TMB), microsatellite instability (MSI), mismatch repair (MSS). Results: Higher expression of RelB was significantly detected in human cancer tissues and a high level of RelB expression was significantly linked with a worse outcome in LGG, KIPAN, ACC, UVM, LUAD,THYM, GBM, LIHC and TGCT but associated with a favorable overall survival (OS) in SARC, SKCM and BRCA. According to the Human Protein Altas database, RelB was considered as an independent factor in breast cancer and renal cancer prognosis. GSEA results revealed that RelB was involved in many oncogenesisrelated processes and immunity-related pathways. RelB was significantly correlated with DNA methylation in 13 types of cancer. Meanwhile, RelB expression was associated with TMB in 5 types of cancer and MSI in 8 types of cancer. In the final, we analyzed the relationship between RelB expression and immune-infiltration cells in human pan-cancer, which suggested RelB could be a promising therapeutic target for cancer immunotherapy. Discussion: Our study further provided insights into a deeper understanding of RelB as a prognostic biomarker., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Wu, Yu, Zhu, Chen, Liu, Yin, Qiang and Xu.)

Background: The morbidity and mortality rates of lung cancer remain high worldwide, and lung adenocarcinoma is one of the most important tissue subtypes of lung cancer. Epidermal growth factor receptor (EGFR) mutation is an important driver gene mutation for lung adenocarcinoma. In recent years, immune checkpoint inhibitors (ICIs), such as programmed cell death 1 (PD-1) and programmed cell death ligand 1 (PD-L1) inhibitors, have achieved remarkable efficacy in some lung cancer patients. Patients with EGFR mutations enjoyed limited benefits from immunotherapy according to recent studies. This study aimed to explore the relationship between EGFR mutation status and the spatial distribution as well as infiltration number of various immune cells in patients with EGFR mutant lung adenocarcinoma., Methods: This study included 62 lung adenocarcinoma patients who underwent surgery. Through multi-point sampling of surgically removed tumor tissues in different areas, 223 tumor tissue samples were finally obtained. We aquired EGFR mutations status including variant allele frequency (VAF) and mutation subtype in each tumor tissue by genetic test. Afterwards, hematoxylin-eosin (HE) staining, immunohistochemical staining and multiplex fluorescence immunohistochemistry staining have been performed, therefore the infiltration of various immune cells and the distribution of tertiary lymphoid structure (TLS) in tumor tissues were obtained by calculating the immunohistochemical score., Results: Compared with EGFR wild-type patients, patients with EGFR-mutant lung adenocarcinoma had more infiltration of CD68+ macrophages and major histocompatibility complex (MHC) class II antigen-presenting cells and higher spatial distribution heterogeneity of MHC class II antigen presenting cells in tumor tissues, while CD56+ natural killer cells and CD8+ T cells had lower infiltration. Tumor tissues with higher EGFR VAF were associated with lower cell infiltration such as CD3+ T cells, CD20+ B cells, CD56+ natural killer cells, CD68+ macrophages, CD8+ T cells, and only CD3+ T cells showed a lower spatial distribution heterogeneity. For the two common subtypes of EGFR mutations in Chinese population, tumor tissues with EGFR exon 19 deletion mutations have lower immune cell infiltration but higher spatial distribution heterogeneity of CD3+ T cells, CD56+ natural killer cells, CD68+ macrophages, and CD8+ T cells than that in EGFR exon 21 L858R mutant tumor tissues. Prognostic analysis found that patients with EGFR mutations with high degree of CD3+ T cells, CD20+ B cell infiltration and larger numbers of TLS formation and high spatial distribution heterogeneity of CD8+ T cell had longer disease-free survival., Conclusions: EGFR-mutated lung adenocarcinoma had a unique "non-inflammatory" tumor microenvironment with low infiltration of immune cells, and there was also heterogeneity in the tumor microenvironment among the tumors with different mutation subtypes and mutation abundance. These differences were not only reflected in the number but also the spatial distribution of immune cell infiltration. Hence, further studies on the immune microenvironment of EGFR-mutant lung adenocarcinoma were of great significance for improving the efficacy of immunotherapy in EGFR-mutant lung adenocarcinoma patients in the future.