Molecular and immune landscape of colorectal liver metastases
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- Institutt for klinisk medisin [10727]
Abstract
Colorectal cancer is a common cancer in both genders, and 50% develop metastases which is the dominating cause of death from CRC, most frequently located in the liver (CLM). Only 20% of patients with CLM are eligible for surgical resection. For the first time in a randomised study, the OSLO-COMET trial compared short-term outcome between open and laparoscopic resection in 280 patients. Laparoscopic resection had a significantly lower complication rate (19% vs 31%), shorter hospital stay (53 vs 96 hours) at a similar cost. The postoperative 90-day mortality was low (0.04%). The long-term outcome after CLM resection may be associated with molecular and immunological features. Based on analysis of samples from the OSLO-COMET biobank the most frequent mutations were located in the TP53, APC, KRAS, PIK3CA, SMAD4, and NRAS genes, and the cohort was enriched for consensus molecular subtype 2. Importantly, the identified transcriptomic changes suggested that immune activation had taken place in tumours exposed to neoadjuvant chemotherapy (NACT). Almost all analysed cases were microsatellite stable, which is associated with poor response to immunotherapy. Quantification of T-cell densities by immunohistochemistry in primary CRC and matched CLM showed low concordance. T-helper cell dominated with regulatory T-cells comprising up to 44%, suggesting immune suppression. T-cells accumulated in the invasive tumour margin, particularly in CLM. A short-interval (<9.5 weeks) between NACT exposure and CLM resection was strongly associated with high T-cell density, including cytotoxic T-cells. In conclusion, the short-term results of the OSLO-COMET trial support the use of laparoscopy for CLM resection. Analyses of molecular and immunological features suggested the presence of immune suppression in CLM, and that NACT induces a transient immune activation that could be exploited in future studies in combination with immune therapy.List of papers
Paper I: Fretland ÅA, Dagenborg VJ, Bjørnelv GMW, Kazaryan AM, Kristiansen R, Fagerland MW, Hausken J, Tønnessen TI, Abildgaard A, Barkhatov L, Yaqub S, Røsok BI, Bjørnbeth BA, Andersen MH, Flatmark K, Aas E, Edwin B. Laparoscopic Versus Open Resection for Colorectal Liver Metastases: The OSLO-COMET Randomized Controlled Trial. Ann Surg. 2018 Feb;267(2):199-207. doi: 10.1097/SLA.0000000000002353. The article is not included in the thesis. Available at: https://doi.org/10.1097/SLA.0000000000002353 |
Paper II: Østrup O, Dagenborg VJ, Rødland EA, Skarpeteig V, Silwal-Pandit L, Grzyb K, Berstad AE, Fretland ÅA, Mælandsmo GM, Børresen-Dale AL, Ree AH, Edwin B, Nygaard V, Flatmark K. Molecular signatures reflecting microenvironmental metabolism and chemotherapy-induced immunogenic cell death in colorectal liver metastases. Oncotarget. 2017 Jul 18;8(44):76290-76304. doi: 10.18632/oncotarget.19350. The article is not included in the thesis. Available at: https://doi.org/10.18632/oncotarget.19350 |
Paper III: Dagenborg VJ, Marshal SE, Grzyb K, Fretland AÅ, Lund-Iversen M, Mælandsmo GM, Børresen-Dale AL, Ree AH, Edwin B, Yaqub S, Flatmark K. Low concordance between T-cell densities in matched primary tumours and liver metastases in colorectal cancer. Manuscript. The article is not included in the thesis. |
Paper IV: Dagenborg VJ, Marshall SE, Yaqub S, Grzyb K, Boye K, Lund-Iversen M, Høye E, Berstad AE, Fretland ÅA, Edwin B, Ree AH, Flatmark K. Neoadjuvant chemotherapy is associated with a transient increase of Intratumoral T-cell density in microsatellite stable colorectal liver metastases. Cancer Biol Ther. 2020 May 3;21(5):432-440. doi: 10.1080/15384047.2020.1721252. Epub 2020 Feb 26. The article is not included in the thesis. Available at: https://doi.org/10.1080/15384047.2020.1721252 |