Project description:A number of immunotherapies, in particular immune checkpoint targeting antibodies and adoptive T-cell therapies, are starting to transform the treatment of advanced cancers. The likelihood to respond to these immunotherapies differs strongly across tumor types, with response rates for checkpoint targeting being the highest in advanced melanoma, renal cell cancer and non-small cell lung cancer. However, also non-responsiveness is observed, indicating the presence of intrinsic resistance or naturally acquired resistance. In addition, a subgroup of patients that do initially respond to immunotherapy will later recur, thereby also pointing towards a role of therapy-induced acquired resistance. Here, we review our current understanding of both intrinsic and acquired resistance mechanisms in cancer immunotherapy, and discuss potential strategies to overcome them.
Project description:In order to identify the direct target of TFEB, we performed a ChIP-seq in HEK293-PFL-TFEB cells where, after removal of tetracycline, samples were collected in duplicates at 18, 36 and 90 hours
Project description:Cancer immunotherapy can induce long lasting responses in patients with metastatic cancers of a wide range of histologies. Broadening the clinical applicability of these treatments requires an improved understanding of the mechanisms limiting cancer immunotherapy. The interactions between the immune system and cancer cells are continuous, dynamic, and evolving from the initial establishment of a cancer cell to the development of metastatic disease, which is dependent on immune evasion. As the molecular mechanisms of resistance to immunotherapy are elucidated, actionable strategies to prevent or treat them may be derived to improve clinical outcomes for patients.
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.
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.
