Project description:Intra-tumour heterogeneity (ITH) foster tumour adaptation and hamper the efficiency of personalised medicine approaches. We investigated the extent of ITH within individual clear cell renal cell carcinomas (ccRCC) by multi-region sampling and copy number analysis. We analyzed 63 tumour regions and 8 normal samples from eight clear cell renal cell carcinomas using Affymetrix SNP6 arrays. All individual tumours were subjected to multi-region sampling and copy-number analysis using Affymetrix SNP6 arrays.
Project description:Successful pancreatic ductal adenocarcinoma (PDAC) immunotherapy necessitates optimization and maintenance of activated effector T cells (Teffs). We prospectively collected and applied multi-omics analysis to paired, pre- and post-treatment PDAC specimens collected in a platform neoadjuvant study of GVAX vaccine +/- nivolumab (anti-PD-1) to uncover sensitivity and resistance mechanisms. We show that GVAX-induced tertiary lymphoid aggregates become immune-regulatory sites in response to GVAX+nivolumab. Higher densities of tumor-associated neutrophils (TANs) following GVAX+nivolumab portend poorer overall survival (OS). Increased T cells expressing CD137 associated with cytotoxic Teff signatures and correlated with increased OS. Bulk and single-cell RNA-sequencing found that nivolumab alters CD4+ T cell chemotaxis signaling in association with CD11b+ neutrophil degranulation, and CD8+ T cell expression of CD137 required for optimal T cell activation. These findings provide new insights into PD-1-regulated immune pathways in PDAC that should inform more effective therapeutic combinations that include TAN regulators and T cell activators.
Project description:Intra-tumour heterogeneity (ITH) foster tumour adaptation and hamper the efficiency of personalised medicine approaches. We investigated the extent of ITH within individual clear cell renal cell carcinomas (ccRCC) by multi-region sampling and copy number analysis. We analyzed 63 tumour regions and 8 normal samples from eight clear cell renal cell carcinomas using Affymetrix SNP6 arrays.
Project description:RNA extracted from the post 72 hour cultured tumor samples from 31 patients with head and neck squamous cell carcinoma treated Nivolumab and Nivolumab+Ipilimumab was analyzed on the nCounter system using the Pan cancer IO360 panel.
Project description:Glioblastoma (GBM) is a highly heterogeneous malignant brain tumour. We took multi-region spatially separated samples from tumours and isolated invasive GBM cells using FACS based on 5ALA of near normal brain parenchyma. RNAseq was then performed to compare expression profiles for tumour cells from different microenvironment.
Project description:We have sampled several tumour regions from a single patient before and after everolimus treatment, including both primary and metastatic site samples to investigate intra-tumour heterogeneity. We selected 4 primary tumour regions, including a pre-treatment biopsy, and 1 metastatic region for expression analysis using microarray data. Two samples were used per region (1 fresh frozen and 1 formalin-fixed).
Project description:Hepatocellular carcinoma (HCC) exhibits diverse aetiologies and molecular heterogeneities, with a median 5-year overall survival (OS) of less than 70% due to late diagnosis and high recurrence rates post-curative ablation or surgery. This study investigated the complex tumor microenvironment (TME) in HCC, emphasizing the interactions between various cell types and their role in disease recurrence. Using samples from the PLANet 1.0 cohort (NCT03267641), spatial transcriptomics were performed on 17 tissue samples from 4 patients, and bulk RNA-seq on multi-region tumour sectors from 91 patients. Analysis revealed extensive intra- and inter-tumour gene expression heterogeneity, identifying a specific subset of endothelial cells (ECs), INTS6+ ECs, enriched and spatially co-localized with tumour cells in primary tumours of recurrent cases. A significant ANGPTL4-SDC1 ligand-receptor interaction was found between INTS6+ ECs and tumour cells. Interestingly, INTS6+ ECs were enriched in histologically annotated microvascular invasion (MVI). These findings suggest novel therapeutic targets focusing on endothelial cell interactions within TME.