Dysregulated Immune and Metabolic Microenvironment Is Associated with the Post-Operative Relapse in Stage I Non-Small Cell Lung Cancer.
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SUBMITTER: Zhang S
PROVIDER: S-EPMC9265031 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:IntroductionThe role of specific immune cell types within the tumor immune microenvironment in non-small cell lung cancer survival is unclear. The potential of these immune cells to become predictive biomarkers of prognosis, and to define subpopulations who will benefit of additional treatment is urgently needed.MethodsStage I to IIIA non-small cell lung cancer patients who underwent surgical resection were queried from the Cancer Genome Atlas; RNAseq data as well as clinical information was extracted. Sample-specific scores for different immune cells were computed via xCell. The association between each cell type and survival was assessed with Cox regression, both unadjusted and adjusted for sex, stage, smoking status, and tumor purity. Models were stratified by lung adenocarcinoma and lung squamous cell carcinoma.ResultsThere were 383 lung adenocarcinoma and 328 lung squamous cell carcinoma samples, and 161 (42%) and 124 (38%) deaths respectively. There was no association between any immune cell infiltrations and survival in the combined unadjusted Cox regression model. After adjustment, the presence of CD8+ cytotoxic T cells (adjusted hazard ratio [HRajd]: 0.84; 95% confidence interval [CI]: 0.71-0.99; P=0.03), CD4+ helper T cells (HRajd: 0.79; 95% CI: 0.66-0.95; P=0.01) and CD20+ B cells (HRajd: 0.80; 95% CI: 0.66-0.97; P=0.02) were significant predictors of decreased risk of death.ConclusionsThis study shows that the adjustment for clinical characteristics is key when evaluating tumor immune infiltration and its association with cancer outcomes. Adjustment for confounding factors modified the prognostic significance of specific immune cell populations in early-stage surgically resected NSCLC cases; clinical attributes may have high relevance on immune infiltration composition.
| S-EPMC8974360 | biostudies-literature
Project description:BackgroundIn Lung adenocarcinoma (LUAD), targeted therapies and immunotherapies have moved from metastatic to early stage and stratification of the relapse risk becomes mandatory. Here we identified a miR-200 based RNA signature that delineates Epithelial-to-mesenchymal transition (EMT) heterogeneity and predicts survival beyond current classification systems.MethodsA miR-200 signature was identified using RNA sequencing. We scored the miR-200 signature by WISP (Weighted In Silico Pathology), used GSEA to identify pathway enrichments and MCP-counter to characterize immune cell infiltrates. We evaluate the clinical value of this signature in our series of LUAD and using TCGA and 7 published datasets.ResultsWe identified 3 clusters based on supervised classification: I is miR-200-sign-down and enriched in TP53 mutations IIA and IIB are miR-200-sign-up: IIA is enriched in EGFR (p < 0.001), IIB is enriched in KRAS mutation (p < 0.001). WISP stratified patients into miR-200-sign-down (n = 65) and miR-200-sign-up (n = 42). Several biological processes were enriched in MiR-200-sign-down tumors, focal adhesion, actin cytoskeleton, cytokine/receptor interaction, TP53 signaling and cell cycle pathways. Fibroblast, immune cell infiltration and PDL1 expression were also significantly higher suggesting immune exhaustion. This signature stratified patients into high-vs low-risk groups, miR-200-sign-up had higher DFS, median not reached at 60 vs 41 months and within subpopulations with stage I, IA, IB, or II. Results were validated on TCGA data on 7 public datasets.ConclusionThis EMT and miR-200-related prognostic signature refines prognosis evaluation independently of tumor stage and paves the way towards assessing the predictive value of this LUAD clustering to optimize perioperative treatment.
| S-EPMC10184345 | biostudies-literature
Project description:For small cell lung cancer (SCLC) therapy, immunotherapy might have unique advantages to some extent. Galectin-9 (Gal-9) plays an important role in antitumor immunity, while little is known of its function in SCLC. By mean of immunohistochemistry (IHC), we tested the expression level of Gal-9 and other immune markers on both tumor cells and tumor-infiltrating lymphocytes (TILs) in 102 surgical-resected early stage SCLC clinical samples. On the basis of statistical analysis and machine learning results, the Gal-9-based immune risk score model was constructed and its predictive performance was evaluated. Then, we thoroughly explored the effects of Gal-9 and immune risk score on SCLC immune microenvironment and immune infiltration in different cohorts and platforms. In the SCLC cohort for IHC, the expression level of Gal-9 on TILs was statistically correlated with the levels of program death-1 (p=0.001), program death-ligand 1 (PD-L1) (p<0.001), CD3 (p<0.001), CD4 (p<0.001), CD8 (p<0.001), and FOXP3 (p=0.047). High Gal-9 protein expression on TILs indicated better recurrence-free survival (30.4 months, 95% CI: 23.7-37.1 vs 39.4 months, 95% CI: 31.6-47.3, p=0.009). The immune risk score model which consisted of Gal-9 on TILs, CD4, and PD-L1 on TILs was established and validated so as to differentiate high-risk or low-risk patients with SCLC. The prognostic predictive performance of immune risk score model was better than single immune biomarker (area under the curve 0.671 vs 0.621-0.644). High Gal-9-related enrichment pathways in SCLC were enriched in immune system diseases and rheumatic disease. Furthermore, we found that patients with SCLC with low immune risk score presented higher fractions of activated memory CD4 T cells than patients with high immune risk score (p=0.048). Gal-9 is markedly related to tumor-immune microenvironment and immune infiltration in SCLC. This study emphasized the predictive value and promising clinical applications of Gal-9 in stage I-III SCLC.
| S-EPMC7577067 | biostudies-literature
Project description:This study aims to characterize tumor-infiltrating macrophages (TAMs), myeloid-derived suppressor cells (MDSC), and the related molecular milieu regulating anti-tumor immunity in limited-stage neuroendocrine (NE)-high and NE-low small cell lung cancer. Primary tumors and matched lymph node (LN) metastases of 32 resected, early-stage SCLC patients were analyzed by immunohistochemistry (IHC) with antibodies against pan-macrophage marker CD68, M2-macrophage marker CD163, and MDSC marker CD33. Area-adjusted cell counting on TMAs showed that TAMs are the most abundant cell type in the TME, and their number in tumor nests exceeds the number of CD3 + T-cells (64% vs. 38% in NE-low and 71% vs. 18% in NE-high). Furthermore, the ratio of CD163-expressing M2-polarized TAMs in tumor nests was significantly higher in NE-low vs. NE-high tumors (70% vs. 31%). TAM density shows a strong positive correlation with CD45 and CD3 in tumor nests, but not in the stroma. fGSEA analysis on a targeted RNAseq oncological panel of 2560 genes showed that NE-high tumors exhibited increased enrichment in pathways related to cell proliferation, whereas in NE-low tumors, immune response pathways were significantly upregulated. Interestingly, we identified a subset of NE-high tumors representing an immune-oasis phenotype, but with a different gene expression profile compared to NE-low tumors. In contrast, we found that a limited subgroup of NE-low tumors is immune-deserted and express distinct cellular pathways from NE-high tumors. Furthermore, we identified potential molecular targets based on our expression data in NE-low and immune-oasis tumor subsets, including CD70, ANXA1, ITGB6, TP63, IFI27, YBX3 and CXCR2.
| S-EPMC8228874 | biostudies-literature
Project description:BackgroundAdjuvant immune checkpoint blockade (ICB) following chemoradiotherapy and adding ICB to chemotherapy have been key advances for stages III-IV non-small cell lung cancer (NSCLC) treatment. However, known biomarkers like PD-L1 are not consistently indicative of ICB response. Other markers within the tumor immune microenvironment (TIME) may better reflect ICB response and/or resistance mechanisms, but an understanding of how TIMEs differ between stage III and IV NSCLC has not been explored.MethodsReal-world data from unresectable, stage III-IV, non-squamous, pretreatment NSCLCs (stage III n = 106, stage IV n = 285) were retrospectively analyzed. PD-L1 immunohistochemistry (IHC) was compared to CD274 gene expression. Then, differential gene expression levels, pathway enrichment, and immune infiltrate between stages were calculated from whole-transcriptome RNA-seq. Analyses were stratified by EGFR status.ResultsPD-L1 IHC and CD274 expression in tumor cells were highly correlated (n = 295, P < 2.2e-16, ⍴ = 0.74). CTLA4 expression was significantly increased in stage III tumors (P = 1.32e-04), while no differences were observed for other ICB-related genes. Metabolic pathway activity was significantly enriched in stage IV tumors (P = 0.004), whereas several immune-related KEGG pathways were enriched in stage III. Stage IV tumors had significantly increased macrophage infiltration (P = 0.0214), and stage III tumors had a significantly higher proportion of CD4 + T cells (P = 0.017). CD4 + T cells were also relatively more abundant in EGFR-mutant tumors vs. wild-type (P = 0.0081).ConclusionDirectly comparing the TIMEs of stage III and IV NSCLC, these results carry implications for further studies of ICB response in non-resectable stage III NSCLC and guide further research of prognostic biomarkers and therapeutic targets.
| S-EPMC9870967 | biostudies-literature
Project description:BackgroundMacrophages are critical players in regulating innate and adaptive immunity in the tumor microenvironment (TME). The prognostic value of macrophages and their heterogeneous phenotypes in non-small cell lung cancer (NSCLC) is still uncertain.MethodsSurgically-resected samples of 681 NSCLC cases were stained by multiplex immunofluorescence to examine macrophage phenotypes as well as the expression levels of program death-ligand 1 (PD-L1) on them in both tumor nest and tumor stroma, including pan-macrophage (CD68+), M1 (CD68+CD163-), and M2 macrophages (CD68+CD163+). Various other immune cell markers, including CD4, CD8, CD20, CD38, CD66B, FOXP3, and CD133, were also evaluated. Machine learning algorithm by Random Forest (RF) model was utilized to screen the robust prognostic markers and construct the CD68-based immune-related risk score (IRRS) for predicting disease-free survival (DFS).ResultsThe expression levels of CD68 were moderately correlated with the levels of PD-L1 (P<0.001), CD133 (P<0.001), and CD8 (P<0.001). Higher levels of CD68 (OR 1.03, 95% CI: 1.01-1.05, P<0.001) as well as M1 macrophage (OR 1.04, 95% CI: 1.01-1.06, P<0.001) indicated shorter DFS. Despite without statiscial significance, intratumoral M2 macrophage (OR 1.05, 95% CI: 0.99-1.10, P=0.081) was also associated with worse DFS. IRRS incorporating three intratumoral CD68-related markers and four intrastromal markers was constructed and validated to predict recurrence (high-risk group vs. low-risk group: OR 2.52, 95% CI: 1.89-3.38, P<0.001). The IRRS model showed good accuracy [area under the curve (AUC) =0.670, 0.709, 0.695, 0.718 for 1-, 3-, 5-year, and overall DFS survival, respectively] and the predictive performance was better than the single-marker model (area under the curve 0.718 vs. 0.500-0.654). A nomogram based on clinical characteristics and IRRS for relapse prediction was then established and exhibited better performance than the tumor-node-metastasis (TNM) classification and IRRS system (C-index 0.76 vs. 0.69 vs. 0.60, 0.74 vs. 0.67 vs. 0.60, 0.81 vs. 0.74 vs. 0.60 of the entire, training, testing cohort, respectively).ConclusionsOur study suggested close interactions between CD68 and other immune markers in TME, demonstrating the prognostic value of CD68 in relapse prediction in resectable NSCLC.
| S-EPMC9073743 | biostudies-literature
Project description:Patients with early-stage non-small cell lung cancer (NSCLC), even stage IA, are at substantial risk of relapse and death. We explored the distinct features of molecular alterations and immune-related gene expression in Formalin-fixed paraffin-embedded (FFPE) samples from 25 relapsed patients compared with 25 non-relapsed patients through using whole-exome sequencing and an immune oncology panel RNA sequencing platform. Results showed that the chemokine, cytolytic activity and tumour-associated antigen gene signatures exhibited significantly higher expression in non-relapsed tumours from stage IA lung adenocarcinoma (LUAD) than that in relapsed tumours. Besides, Kaplan-Meier survival analysis revealed that the gene signatures of chemokines and tumour-associated antigens were significantly associated with the patients' disease-free survival (DFS), indicating their prognostic value in early-stage LUAD. Cytolytic activity displayed a similar trend but failed to reach statistical significance. These findings revealed a weakened immune phenotype in relapsed tumours and provide valuable information for improving the treatment management of these high-risk patients. Due to the overall small patient number in this study, these differences should be further validated in a larger cohort.
| S-EPMC7689326 | biostudies-literature
Project description:BackgroundSarcopenia is among the most prevalent and serious cancer-related symptom, and is strongly correlated with a poor prognosis. Moreover, it reportedly predicts poor prognosis after surgery in patients with lung cancer. However, it is unclear whether sarcopenia directly affects post-operative recurrence. The purpose of this study was to evaluate whether sarcopenia can be a risk indicator for post-operative recurrence, and whether it suppresses anti-tumor immunity, in a cohort of patients with resected non-small cell lung cancer.MethodsThis study retrospectively reviewed the data of 256 consecutive patients who underwent curative lobectomy and lymph node dissection for non-small cell lung cancer at our institution. The psoas muscle mass index was calculated as the total psoas muscle area at the third lumbar vertebral level/height2 (cm2/m2). Sarcopenia was defined by a psoas muscle mass index of under 5.03 cm2/m2 and 3.17 cm2/m2 in male and female patients, respectively. Post-operative prognosis and cumulative incidence of recurrence rates were calculated.ResultsThe 5-year overall survival and disease-free survival rates post-surgery were 59.5% and 38.6%, respectively, in patients with sarcopenia versus 81.1% and 72.1%, respectively, in patients without sarcopenia (p < 0.001). The 5-year cumulative incidence of recurrence rate in patients with sarcopenia was significantly higher than those without sarcopenia (49.9% versus 22.4%, respectively) in every pathological stage. Pathological stages II and III (hazard ratio, 3.36; p = 0.004), histological type (hazard ratio, 2.31; p = 0.025), and sarcopenia (hazard ratio, 2.52; p = 0.001) were independent risk factors for post-operative recurrence according to multivariate analysis.ConclusionSarcopenia is a risk indicator for post-operative recurrence in patients with non-small cell lung cancer.
| S-EPMC8457491 | biostudies-literature
Project description:Non-small lung cancer (NSCLC) has been defined as a highly life-threatening heterogeneous disease, with high mortality and occurrence. Recent research has indicated that tumor-infiltrating lymphocytes play a key determinant role in cancer progression. Emerging single-cell RNA sequencing (also termed scRNA-seq) has been extensively applied to depict the baseline landscape of the cell composition and function phenotype in the tumor environment (TME). Herein, we dissected the cell types in NSCLC samples (including tissue and blood) and identified three types of cell marker genes including cancer cells, T cells, and macrophages by integrating two NSCLC-associated scRNA-seq datasets in GEO. Survival analysis indicated that 17 marker genes were related to tumor prognosis. Function annotation was used to scrutinize the molecular mechanism of these marker genes in different cells. Besides, we investigated the developmental trajectory and T cell receptor repertoire diversity of tumor-infiltrating T cells. Our analysis will help further understand the complexity of cell components and the heterogeneity of TME in NSCLC.
| S-EPMC10637824 | biostudies-literature
Project description: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.
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