INCEPTOR · Investigate the mode of action ofInvestigate the mode of action of beta-carboline derivative Harmine on increasing MHC-I expression and potentiating the Immune Checkpoint Blockade cancer immunotherapy

Investigate the mode of action ofInvestigate the mode of action of beta-carboline derivative Harmine on increasing MHC-I expression and potentiating the Immune Checkpoint Blockade cancer immunotherapy

Colorectal cancer (CRC) is a malignant tumor that forms in the tissues of the colon (large intestine) or rectum (the digestive system's final part). In 2020, the European Cancer Information System (ECIS) estimated that CRC made up 12.7% of new cancer diagnoses (150,366 in women and 191,053 in men). It also accounted for 12.4% of all cancer deaths (https://ecis.jrc.ec.europa.eu, accessed 15/01/2021). CRC risk increases with age, and most cases occur in people over 50 years. In the EU-27, the estimated lifetime risk (ages 0-74) is 1 in 35 for women, and 1 in 22 for men. In the 70+ age group, 195,667 cases were recorded. Treating CRC remains particularly difficult in advanced stages. The outlook for patients is poor, and options for therapy are limited. In the past decade, immune checkpoint inhibitors (ICIs) have transformed cancer care. These treatments reawaken the body's immune system to fight tumors. However, they help only a small fraction of CRC patients—roughly 15–20%—whose tumors have specific genetic features (high microsatellite instability, MSI-H). The other 80–85% have tumors classified as microsatellite-stable (MSS). These are largely invisible to the immune system and unresponsive to immunotherapy. Research has studied why CRC-MSS tumors evade immune attack. A key mechanism of the immune evasion is a failure of tumor antigen presentation. For the immune system to recognize and destroy a cancer cell, the cell must display fragments of abnormal proteins on its surface via molecules of the major histocompatibility complex class I (MHC-I). In MSS cancers, this display system often shuts down. Without MHC-I signals, the immune system's killer cells (CD8⁺ cytotoxic T lymphocytes) cannot identify or attack the tumor. Modifying these silent tumors so the immune system can detect and destroy them is a major priority in cancer research. The INCEPTOR project aimed to address this challenge by studying ACB1801, a harmine derivative and naturally occurring beta-carboline alkaloid. Previous work by the research group suggested harmine increases MHC-I expression on tumor cells. This could make tumors visible to immune cells. The fellowship's main aim was to clarify how ACB1801 reprogrammed the tumor microenvironment. This environment is a complex network of immune and non-immune cells surrounding a tumor. The project also tested, in preclinical models, whether combining ACB1801 with an anti-PD-1 ICB could create a stronger anti-tumor response than either treatment alone. The project pursued three connected objectives. First, map the molecular mechanisms by which ACB1801 boosts antigen processing and presentation in CRC cells. Second, assess the drug's effects on immune cell populations in the tumor microenvironment using mouse models of MSS colorectal cancer. Third, generate proof-of-concept data on whether harmine can enhance the efficacy of dendritic cell vaccination. In this approach, the patient's antigen-presenting cells are loaded with tumor proteins and reinfused to trigger a targeted immune response. This project sits at the intersection of cancer immunology, molecular biology, and translational medicine. Its relevance is high: MSS colorectal cancer affects hundreds of thousands of patients each year in Europe. No effective immunotherapy exists for this group. The INCEPTOR fellowship took place at the Luxembourg Institute of Health (LIH). It was supported by the Marie Skłodowska-Curie Actions Postdoctoral Fellowship program. The project involved a collaboration with AC BioScience (Switzerland) and scientific partners in France and Luxembourg.

Текст от CORDIS, на английски · Данни: CORDIS, © Европейски съюз