Research project funded by the German Hiege Foundation
Immunotherapies offer new perspectives in the treatment of cancer. Unfortunately, tumor immune-escape mechanisms limit their effectiveness on a long turn. The intracellular receptor NLRC5 impacts the regulation of tumor recognition by the immune system in melanoma and other entities and is hence at the core of a new research project by ImmunoSensation² member Dr. Nicole Glodde from the Institute of Experimental Oncology at the University Hospital Bonn. The project is funded by the German Hiege Foundation, providing 30.000 € over the period of one year.
Adaptive T-Cell therapy (ACT) is a type of Immunotherapy, applicable for the treatment of various cancer types. Patients own T-cells are isolated from their blood or tumor tissue and adopted in a way enabling them to specifically recognize and eliminate the tumor cells. This is achieved by engineering the T-cells to express tailor-made T-Cell receptors (TCRs) that recognize peptide epitopes of antigens encoded by the respective target tumor. Subsequently, the adopted T-Cells are re-administered to the patient in order to fight the tumor. Unfortunately, durable responses to ACT are often limited by tumor immune escape.
Tumors evade the immune system
To keep the immune system informed about their health status, cells constantly present antigens from their interior on their surface, using so called MHC-Molecules. Tumors can escape the immune system by e.g. reducing or losing MHC-I molecules on the cell surface. “This prevents the recognition by CD8+ T-Cells and promotes melanoma recurrence after immunotherapy” explains Dr. Nicole Glodde, group leader at the Institute of Experimental Oncology. Conversely, a decrease in MHC-I molecules can render cancer cells susceptible to recognition and destruction by NK cells. The specific MHC threshold for NK cell-mediated anti-tumor response is largely unknown.
A renown factor determining the level of MHC-I expression is the cellular receptor NLRC5 (NOD-like receptor family CARD domain containing 5). “Low NLRC5 expression in melanoma patients is associated with poor prognosis” Dr. Glodde states. “This is due to a reduced infiltration of the tumor tissue by cytotoxic anti-tumor cells and thus a poor response to immune checkpoint blockade. “
Unraveling the role of NLRC5 in tumor progression
Until today, the role of NLRC5 in MHC-I expression and tumor progression is poorly understood. “Recently, we discovered a spontaneous loss-of-function mutation in NLRC5 in immunotherapy-recurrent mouse melanoma cells. This mutation resulted in decreased MHC-I induction, thereby promoting resistance to T-cell-based immunotherapy and the development of recurrence.” states Dr. Glodde. However, why the mutated NLRC5 melanomas are not destroyed by NK cells despite reduced MHC-I expression remains unclear.
Dr. Glodde and her team want to better understand the role of NLRC5 as a fine-tuner of MHC-expression and thus for CD8+ T- and NK cell-induced immune response against melanomas and identify additional mechanisms that hinder NK-cell-mediated anti-tumor responses. To do so, the scientists want to use preclinical melanoma models, human and murine melanoma cell lines, and state-of-the-art genome editing technologies. “We hope to identify an innovative treatment approach to improve therapy and to overcome immunotherapy resistance of melanoma and other cancer patients carrying a mutation in NLRC5” Dr. Glodde closes.
Funding by German skin cancer Foundation
The promising research project lead by Dr. Nicole Glodde is now funded by the renowned Hiege Foundation. To promote research and the development of new treatment approaches for skin cancer, especially melanoma, the Hiege Foundation funds several, selected research projects each year. The funding with a volume of 30.000 € is provided in the sense of start-up financing to get new project ideas off the ground. "I am very pleased that this funding will allow me and my team to get to the bottom of the issues at hand."
Dr. Nicole Glodde
Institute of Experimental Oncology
Phone: +49 228 287 51192