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Global evolution of the tumor microenvironment associated with progression from preinvasive invasive to invasive human lung adenocarcinoma.

ABSTRACT: To investigate changes in the tumor microenvironment (TME) during lung cancer progression, we interrogate tumors from two chest computed tomography (CT)-defined groups. Pure non-solid (pNS) CT density nodules contain preinvasive/minimally invasive cancers, and solid density nodules contain invasive cancers. Profiling data reveal a dynamic interaction between the tumor and its TME throughout progression. Alterations in genes regulating the extracellular matrix and genes regulating fibroblasts are central at the preinvasive state. T cell-mediated immune suppression is initiated in preinvasive nodules and sustained with rising intensity through progression to invasive tumors. Reduced T cell infiltration of the cancer cell nests is more frequently associated with preinvasive cancers, possibly until tumor evolution leads to a durable, viable invasive phenotype accompanied by more varied and robust immune suppression. Upregulation of immune checkpoints occurs only in the invasive nodules. Throughout progression, an effector immune response is present but is effectively thwarted by the immune-suppressive elements.

SUBMITTER: Altorki NK

PROVIDER: S-EPMC9033258 | biostudies-literature | 2022 Apr

REPOSITORIES: biostudies-literature

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Global evolution of the tumor microenvironment associated with progression from preinvasive invasive to invasive human lung adenocarcinoma.

Altorki Nasser K NK Borczuk Alain C AC Harrison Sebron S Groner Lauren K LK Bhinder Bhavneet B Mittal Vivek V Elemento Olivier O McGraw Timothy E TE

Cell reports 20220401 1

To investigate changes in the tumor microenvironment (TME) during lung cancer progression, we interrogate tumors from two chest computed tomography (CT)-defined groups. Pure non-solid (pNS) CT density nodules contain preinvasive/minimally invasive cancers, and solid density nodules contain invasive cancers. Profiling data reveal a dynamic interaction between the tumor and its TME throughout progression. Alterations in genes regulating the extracellular matrix and genes regulating fibroblasts are ...[more]

PMID: 35385730

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Project description:Lung adenocarcinoma (LUAD) is a heterogeneous disease. Our study aimed to understand the unique molecular features of preinvasive to invasive LUAD subtypes. We retrospectively analyzed the clinical, histopathological, and molecular data of 3,254 Chinese patients with preinvasive lesions (n = 252), minimally invasive adenocarcinomas (n = 479), and invasive LUAD (n = 2,523). Molecular data were elucidated using a targeted 68-gene next-generation sequencing panel. Our findings revealed four preinvasive lesion-predominant gene mutations, including MAP2K1 insertion-deletions (indels), BRAF non-V600E kinase mutations, and exon 20 insertions (20ins) in both EGFR and ERBB2, which we referred to as mutations enriched in AIS (MEA). The detection rate of MEA in invasive tumors was relatively lower. MAP2K1 missense mutations, which were likely passenger mutations, co-occurred with oncogenic driver mutations, while small indels were mutually exclusive from other genes regardless of the invasion level. BRAF non-V600E kinase-mutant invasive adenocarcinomas (IAC) had significantly higher mutation rates in tumor suppressor genes but lower frequency of co-occurring oncogenic driver mutations than non-kinase-mutant IAC, suggesting the potential oncogenic activity of BRAF non-V600E kinase mutations albeit weaker than BRAF V600E. Moreover, similar to the extremely low frequency of MAP2K1 indels in IAC, BRAF non-V600E kinase domain mutations co-occurring with TSC1 mutations were exclusively found in preinvasive lesions. Compared with EGFR L858R and exon 19 deletion, patients with preinvasive lesions harboring 20ins in either EGFR or ERBB2 were significantly younger, while those with IAC had similar age. Furthermore, our study demonstrated distinct mutational features for subtypes of oncogene mutations favored by different invasion patterns in adenocarcinomas. In conclusion, our data demonstrate distinct mutational features between preinvasive lesions and invasive tumors with MEA, suggesting the involvement of MEA in the early stages of tumorigenesis. Further pre-clinical studies are required to establish the role of these genes in the malignant transformation of LUAD.

Project description:BackgroundOnly a fraction of lung adenocarcinoma (LUAD) patients are eligible for immunotherapy. The identification of biomarkers for immunotherapy is crucial to improve patient outcomes. This study aims to systemically analyze LRP1B mutation and its association with the tumor immune microenvironment (TIME) and immunotherapy.MethodsA cohort of immune checkpoint inhibitors (ICIs)-treated LUAD patients was analyzed to assess the association of LRP1B mutation with immunotherapy prognosis. Another cohort of LUAD patients with genetic and transcriptomic data was also obtained from The Cancer Genome Atlas (TCGA). By investigating the ICIs and the TCGA-LUAD cohorts, we compared the differences in mutation profiles, immunogenicity, TIME, and DNA damage repair (DDR) mutations between the LRP1B-mutated and LRP1B wild-type groups. Additionally, we performed multiplex immunohistochemistry (mIHC) to validate the differences in the tumor microenvironment.ResultsOur results revealed that LRP1B mutation is associated with multiple immune-related pathways. Analysis of TIME indicated that LUAD patients with LRP1B mutation expressed significant levels of genes involved in antigen presentation, cytotoxicity, chemokines, and pro-inflammatory mediators, whereas a few immune checkpoint genes were highly expressed in the LRP1B-mutated group as well. Cell-type Identification by Estimating Relative Subsets of RNA Transcripts (CIBERSORT) analysis indicated that LRP1B-mutated LUAD patients had higher infiltration of active immune cells. Multiplex IHC analysis showed that LRP1B-mutated LUAD patients had elevated programmed death ligand-1 (PD-L1) expression and immune cell infiltration. Patients with LRP1B mutation had higher tumor mutation burden, neoantigens, as well as more mutated genes in the DDR-related pathways. Finally, LRP1B-mutated LUAD patients showed a significant prolongation of progression-free survival (PFS) in the ICIs cohort and could be effectively predicted by our constructed nomogram.ConclusionsOur study suggests that LRP1B mutation is associated with higher immune cell infiltration and elevated immune gene expression in TIME and potentially serves as a prognostic biomarker for LUAD patients treated with ICIs.

Project description:Background: 7-Methylguanosine (m7G) is an important posttranscriptional modification that regulates gene expression and is involved in tumorigenesis and development. Tumor microenvironment has been proven to be highly involved in tumor progression and prognosis. However, how m7G-associated genes affect the tumor microenvironment of patients with lung adenocarcinoma (LUAD) remains to be further clarified. Methods: The genetic alterations of m7G-associated genes and their associations with the prognosis and tumor microenvironment in LUAD patients were systemically analyzed. An m7G-Riskscore was established and analyzed for its performance in disease prognosis and association with patient response to immunotherapy. Expression of the model genes at the protein level was investigated through ex vivo experiments. A nomogram was finally obtained based on the m7G-Riskscore and several significant clinical pathological features. Results: m7G-Associated genes were obtained from five LUAD datasets from The Cancer Genome Atlas and Gene Expression Omnibus databases, and their expression pattern was determined. Based on the m7G-associated genes, three LUAD clusters were defined. The differentially expressed genes from the three clusters were screened and used to further divide the LUAD patients into two gene clusters. It was demonstrated that the alterations of m7G-associated genes were associated with the clinical pathological features, prognosis, and tumor immune infiltration in LUAD patients. An m7G-Riskscore including CAND1, RRM2, and SLC2A1 was obtained with robust and accurate prognostic performance. WB and cell immunofluorescence also showed significant dysregulation of CAND1, RRM2, and SLC2A1 in LUAD. In addition, a nomogram was established to improve the clinical feasibility of the m7G-Riskscore. Correlation analysis revealed that patients with a lower m7G-Riskscore had higher immune and stromal scores, responded well to chemotherapeutics and multiple targeted drugs, and survived longer. Patients with a higher m7G-Riskscore tended to suffer from a higher tumor mutation burden. Furthermore, the m7G-Riskscore exhibited significant associations with immune cell infiltration and cancer stemness. Conclusion: This study systemically analyzed m7G-associated genes and identified their potential role in tumor microenvironment and prognosis in patients with LUAD. The findings of the present study may help better understand LUAD from the m7G perspective and also provide a new thought toward the prognosis and treatment of LUAD.

Dataset Information

Global evolution of the tumor microenvironment associated with progression from preinvasive invasive to invasive human lung adenocarcinoma.

Publications

Global evolution of the tumor microenvironment associated with progression from preinvasive invasive to invasive human lung adenocarcinoma.

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