Project description:Comparing the relative proportions of immune cells in tumor and adjacent normal tissue from NSCLC patients demonstrates the early changes of tumor immunity and provides insights to guide immunotherapy design. We mapped the immune ecosystem using computational deconvolution of bulk transcriptome data from the Cancer Genome Atlas (TCGA) and single cell RNA sequencing (scRNA-seq) data of dissociated tumors from early-stage non-small cell lung cancer (NSCLC) to investigate early immune landscape changes occurring during tumorigenesis. Computational deconvolution of immune infiltrates in 44 NSCLC and matching adjacent normal samples from TCGA showed heterogeneous patterns of alterations in immune cells. The scRNA-seq analyses of 11,485 cells from 4 treatment-naïve NSCLC patients comparing tumor to adjacent normal tissues showed diverse changes of immune cell compositions. Notably, CD8+ T cells and NK cells are present at low levels in adjacent normal tissues, and are further decreased within tumors. Myeloid cells exhibited marked dynamic reprogramming activities, which were delineated with differentiation paths through trajectory analysis. A common differentiation path from CD14+ monocytes to M2 macrophages was identified among the 4 cases, accompanied by up-regulated genes (e.g. ALCAM/CD166, CD59, IL13RA1, IL7R) with enriched functions (adipogenesis, lysosome), and down-regulated genes (e.g. CXCL2, IL1B, IL6R) with enriched functions (TNFa signaling via NF-kB, inflammatory response). Computational deconvolution and single cell sequencing analyses have revealed a highly dynamic immune reprogramming that occurs in early stage NSCLC development, suggesting that normalizing both immune compartments may represent a viable strategy for treatment of early stage cancer and prevention of progression.
Project description:The overall objective of this study was to characterize the diversity and ontogeny of CD8 T cells in untreated lung tumors. This was accomplished by performing bulk RNAseq and flow cytometry analysis on CD8+ T cell subsets isolated from tumor tissue, normal adjacent to tumor (juxta0 tissue samples from patients undergoing surgical resection for early-stage, untreated non-small-cell lung cancer (NSCLC).
Project description:Success of immune checkpoint inhibitors in advanced non-small cell lung cancer (NSCLC) has invigorated their use in neo-adjuvant setting for early-stage disease. However, the cellular and molecular mechanisms of the early immune responses to therapy remain poorly understood. Through an integrated analysis of early-stage NSCLC patients and a Kras-mutant mouse model, we show a prevalent programmed cell death 1/ programmed cell death 1 ligand 1 (PD-1/PD-L1) axis exemplified by increased intratumoral PD-1+ T cells and PD-L1 expression. Notably, tumor progression was associated with spatiotemporal modulation of the immune microenvironment. Importantly, PD-1 inhibition controlled tumor growth, improved overall survival, and reprogrammed tumor-associated lymphoid and myeloid cells. Depletion of T lymphocyte subsets demonstrated synergistic effects of those populations on PD-1 inhibition of tumor growth. Transcriptome analyses revealed T cell subset-specific alterations corresponding to degree of response to the treatment. These results provide insights into temporal evolution of the phenotypic effects of PD-1/PD-L1 activation and inhibition, and motivate targeting this axis early in lung cancer progression.
Project description:Gene expression profiling of NSCLC tissues let to the establishment of several prognostic, predictive gene signatures with little overlap. To study factors introducing variability into gene expression microarray studies we compared interpatient (patient-to-patient) and intrapatient (tumor sub-sample) variations in gene expression profiles in stage I and II NSCLC tissues. We identified 128 probe sets which showed variable intratumoral expression
Project description:We identified a tumor signature of 5 genes that aggregates the 156 tumor and normal samples into the expected groups. We also identified a histology signature of 75 genes, which classifies the samples in the major histological subtypes of NSCLC. A prognostic signature of 17 genes showed the best association with post-surgery survival time. The performance of the signatures was validated using a patient cohort of similar size
Project description:Gene expression profiling of NSCLC tissues let to the establishment of several prognostic, predictive gene signatures with little overlap. To study factors introducing variability into gene expression microarray studies we compared interpatient (patient-to-patient) and intrapatient (tumor sub-sample) variations in gene expression profiles in stage I and II NSCLC tissues. We identified 128 probe sets which showed variable intratumoral expression Four different sites (A,B,C,D) of individual primary tumors and matched distant normal lung tissue (N) from 20 patients were used to establish gene expression patterns captured by Affymetrix HG-U133 Plus 2.0 arrays (n = 100).
Project description:We launched an investigator-initiated, Simon’s two-stage design trial of neoadjuvant sintilimab combined with carboplatin and nab-paclitaxel (nab-PC) in early-stage EGFR-mutant NSCLC (Clinicaltrial.gov number NCT05244213). Here we report the first interim results of stage 1 cohort which met the overall primary endpoint in advance, and multi-omics profiling of neoadjuvant immunotherapy combination in early-stage EGFR-mutant patients. We performed in-depth single-cell RNA/TCR sequencing (scRNA/TCR-seq) of cells derived from 11 resected tumors as well as 34 tumors from real-world cohort which were all confirmed wild-type lung adenocarcinoma (LUAD) or adeno-squamous carcinoma (ASC) and received neoadjuvant immunochemotherapy as control. By associating the tumor microenvironment (TME) and with responses, we uncovered heterogeneous mechanisms of primary resistance, providing insights into further strategic developments of combination regimens to improve the clinical outcome of EGFR-mutant NSCLC patients.
Project description:We identified a tumor signature of 5 genes that aggregates the 156 tumor and normal samples into the expected groups. We also identified a histology signature of 75 genes, which classifies the samples in the major histological subtypes of NSCLC. A prognostic signature of 17 genes showed the best association with post-surgery survival time. The performance of the signatures was validated using a patient cohort of similar size A genome-wide gene expression analysis was performed on a cohort of 91 patients. We used 91 tumor- and 65 adjacent normal lung tissue samples. We defined sets of predictor genes (probe sets) with the expression profiles. The power of predictor genes was evaluated using an independent cohort of 96 non-small cell lung cancer- and 6 normal lung samples
Project description:Eighty-four completely resected stage I/II non-small cell lung cancer (NSCLC) without adjuvant therapy were profiled using whole genome expression microarrys in order to identify novel classifications associated with RFS. Association with relapse-free survival (RFS) and clinicopathological parameters was assessed. An external cohort of 162 tumors was used to validate results.