Project description:Although immunotherapy with PD-(L)1 blockade is routine for lung cancer, little is known about acquired resistance. Among 1,201 patients with non-small cell lung cancer (NSCLC) treated with PD-(L)1 blockade, acquired resistance is common, occurring in >60% of initial responders. Acquired resistance shows differential expression of inflammation and interferon (IFN) signaling. Relapsed tumors can be separated by upregulated or stable expression of IFNγ response genes. Upregulation of IFNγ response genes is associated with putative routes of resistance characterized by signatures of persistent IFN signaling, immune dysfunction, and mutations in antigen presentation genes which can be recapitulated in multiple murine models of acquired resistance to PD-(L)1 blockade after in vitro IFNγ treatment. Acquired resistance to PD-(L)1 blockade in NSCLC is associated with an ongoing, but altered IFN response. The persistently inflamed, rather than excluded or deserted, tumor microenvironment of acquired resistance informs therapeutic strategies to effectively reprogram and reverse acquired resistance.
Project description:HD and control patient-derived induced pluripotent stem cells were used to generate medium spiny neuron-like cells. Three control in triplicate, one control in duplicate, one HD samples with CAG repeat length in typical adult onset range in triplicate and one in duplicate, and five HD samples with CAG repeat length in typical juvenile onset range in triplicate were differentiated as biological growth replicate (separate differentiations) into medium spiny neuron-like cells. Total RNA was isolated using the Qiagen RNeasy Kit and QIAshredders for cell lysis. 1 µg of RNA with RIN values >9 were used for library preparation using the strand specific Illumina TruSeq Total RNA protocol. Libraries were sequenced on the HiSeq 2500 using 100 cycles to obtain paired-end 100 reads at >50M reads per sample.
Project description:We identify a profoundly remodelled TME in targeted therapy resistant (RTT) tumours. We provide bulk transcriptomic data of targeted therapy naive (NTT) and RTT tumours of 3 murine models. Additionally, we provide low-input sequencing of CD103+ dendritic cells and T cells from NTT and RTT Braf/Pten tumours. We identified that in RTT cell lines the MAPK pathway is reactivated and provide SLAM-seq data to determine transcriptional targets of MAPK pathway inhibition in NTT and RTT cell lines. We also provide ATAC-Seq data of NTT and RTT cell lines sorted from tumors of the Braf/Pten melanoma model.
