Project description:we investigated the spatial features of surgically-removed biopsies from multiple loci in tumor masses of 15 patients with non-small cell lung cancer (NSCLC). We observed that the immune microenvironment is highly spatial heterogeneous such that intra-tumoral regional variation is as large as inter-personal variation. While the local mutational burden was associated with local T cell clonal expansion, observed local anti-tumor cytotoxicity is strongly associated with local tumoral circumstance rather than TMB alone
Project description:Small-cell lung cancer (SCLC) is the most fatal form of lung cancer. Intra-tumoral heterogeneity, marked by neuroendocrine (NE) and non-neuroendocrine (non-NE) cell states, defines SCLC, but the drivers of SCLC plasticity are poorly understood. To map the landscape of SCLC tumor microenvironment (TME), we apply spatially resolved transcriptomics and quantitative mass spectrometry-based proteomics to metastatic SCLC tumors obtained via rapid autopsy. The phenotype and overall composition of non-malignant cells in the tumor microenvironment (TME) exhibits substantial variability, closely mirroring the tumor phenotype, suggesting TME-driven reprogramming of NE cell states. We identify cancer-associated fibroblasts (CAF) as a crucial element of SCLC TME heterogeneity, contributing to immune exclusion, and predicting an exceptionally poor prognosis. Together, our work provides the first comprehensive map of SCLC tumor and TME ecosystems, emphasizing their pivotal role in SCLCs adaptable nature, opening possibilities for re-programming the intercellular communications that shape SCLC tumor states.
Project description:Hypoxia triggers aggressive cancer growth and contributes to chemotherapy resistance. Novel therapeutic strategies aim at targeting hypoxia activated signaling pathways. Tumor hypoxia not only affects neoplastic tumor cells but also the surrounding stroma cells. Therefore, a novel ex vivo model was established, which allows the study of hypoxia effects in fragments of non-small cell lung cancer (NSCLC) with preserved tumor microenvironment and 3D-structure. Microarray analysis identified 107 significantly regulated genes with at least two-fold expression change in hypoxic compared to normoxic fragments. However, only four genes were significantly regulated in both subtypes, adenocarcinoma and squamous cell carcinoma. The hypoxic regulation of these four genes was verified in an independent set using quantitative PCR. Non-small cell lung cancer (NSCLC) fragments were cultured ex vivo under hypoxia or normoxia for three days. cDNA microarray analysis was performed in hypoxic and normoxic lung cancer fragments from ten patients.
Project description:To evaluate the characteristics of the tumor immune-microenvironment in brain metastases of non-small-cell lung cancer (NSCLC), we investigated the immunophenotype of primary NSCLC and its brain metastasis.
Project description:One key barrier to improving efficacy of personalized cancer immunotherapies that are dependent on the tumor antigenic landscape remains patient stratification. While patients with CD3+CD8+ T cell inflamed tumors typically show better response to immune checkpoint inhibitors, it is still unknown if the repertoire of HLA bound peptides presented in highly inflamed and non-inflamed tumors is substantially different. We surveyed 61 tumor regions and adjacent non-malignant lung tissues from eight lung cancer patients and performed deep antigen discovery combining immunopeptidomics, genomics, bulk and spatial transcriptomics and explored the heterogeneous expression and presentation of tumor (neo)antigens. Here we associated diverse immune cell populations with the immunopeptidome in CD3+CD8+ T cell excluded, infiltrated, highly- and lowly-inflamed tumors. We found evidence for lower immune-editing and higher presentation efficiency of tumor-associated antigens in lowly-inflamed and CD3+CD8+ T cell excluded tumors. This could have implications for the choice of combination therapies tailored to the patient’s mutanome and microenvironment.
