Research
The TSMI group has three main avenues of research, all of which involve harnessing the immune system to target and kill cancer cells:
1. Matrix Immunology in the TME
The extracellular matrix has been proven to be a key component to the tumor microenvironment (TME), this is partcilularly evident in highly desmoplastic tumors such as pancreatic ductal adenocarcinoma. This dense, collagen-rich matrix can both disclude immune cells from interacting with target cancer cells whilst concomittantly downregulating their anti-cancer phenotype. The TSMI group aims to further understand how the extracellular matrix can directly regulate immune cell function in the TME.
2. Identification of novel immunosuppresive targets involved in primary and acquired resistance to ICB
ICB has revolutionized cancer treatment, achieving cures in specific cancer types. However, many patients exhibit primary or acquired resistance to these therapies. Through in vivo models, we have identified immunosuppressive molecules and mechanisms contributing to this resistance. Ongoing investigations are targeting these mechanisms to determine if overcoming resistance to ICB is possible.
3. Drug repurposing in combination with ICB
Drug repurposing in combination with ICB aims to enhance cancer treatment by using existing drugs to improve patient responses and overcome resistance to ICB. We have shown that the beta-blocker propranolol, traditionally used for cardiovascular conditions, can enhance the efficacy of ICB (Fjæstad et al, 2022). Currently, a phase 2 trial is testing the efficacy of combining propranolol and pembrolizumab in patients with sarcoma.
Group leader Daniel H. Madsen is the head of the Herlev Hospital Animal Research Facility, which is used to complete in vivo studies of tumourigenesis using both conventional mouse models and transgenic models to elucidate the immunological mechanisms behind cancer and the response to therapies. These methods include subcutaneous, orthotopic, spontaneous, metastastic and transgenic mouse models of cancer. Advanced procedures such as fine needle aspirate biopsies have been established in the facility. To compliment this in vivo work, we have privileged access to the CCIT-DK Biobank, a unique repository containing tumor and immune cell samples from approximately 200 individual patients with various cancer types, examples in Gokuldass et al., Cancers 2020. Our laboratory employs several key methodologies, including RNA and Whole genome sequencing, high dimensional flow cytometry, co-culture assays, real-time cytotoxicity assays, genome editing, patient-derived models and 3D ex vivo matrix models. In addition to the key research objectives, the TMSI group strives to promote a positive, fun and supportive research enviroment.