In a new study published in Molecular Oncology, researchers have discovered a novel mechanism to enhance the body’s immune response to tumors. The study is a result of collaboration between Sprint Bioscience, Karolinska institutet, the Luxembourg Institute of Health and Deciphera Pharmaceuticals, and was included as a manuscript in Yasmin Yu’s PhD thesis at the Department of Oncology-Pathology in 2021.
A dual attack on cancer’s defenses
Cancer cells are notorious for creating an immunosuppressive environment that shields them from the body’s natural defenses. Inhibition of cellular recycling mechanism – autophagy – by targeting selectively a key protein VPS34 leads to an increase in specific chemokines, CCL5 and CXCL10, which act like beacons, guiding immune cells to the tumor site. The study now demonstrate that it is triggering of a type I Interferon pathway through cGAS-STING activation, which is the underlying molecular mechanism. When combined with STING agonists, VPS34 inhibition further increased cytokine production and anti-tumor effects in a melanoma mouse model. Thus, an activation of a pro-inflammatory response and an enhanced recruitment of immune cells not only hampers tumor growth but can also improve the effectiveness of an existing immunotherapy. Understanding of the molecular mechanisms behind the action of VPS34 inhibition and promising results of combination with immune therapy in mouse models may pave the way for clinical trials in humans.
Angelo De Milito, PhD, Director Tumor Biology and Therapeutics at Sprint Bioscience and associated with the Department of Oncology-Pathology, says: “This publication as well as the work performed by Yasmin Yu during her doctoral studies result from a close, stimulating and productive collaboration between industrial and academic partners and show how such collaborative projects may have a positive impact in terms of education, scientific knowledge and innovation. Such advancement in understanding the role of VPS34 in modulating type I interferon signaling provides a scientific rationale to investigate combination therapies with different classes of immune-activating agents.”
Publication
Yu Y, Bogdan M, Noman MZ, Parpal S, Bartolini E, Van Moer K, Kleinendorst SC, Bilgrav Saether K, Trésaugues L, Silvander C, Lindström J, Simeon J, Timson MJ, Al-Hashimi H, Smith BD, Flynn DL, Alexeyenko A, Viklund J, Andersson M, Martinsson J, Pokrovskaja Tamm K, De Milito A, Janji B
Mol Oncol 2024 Mar;():
