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FRIMEDBIO-Fri prosj.st. med.,helse,biol

High-dimensional analysis of AXL-mediated immunotherapy resistance: Clinical translation for personalized medicine

Alternativ tittel: Høydimensjonell analyse av AXL-mediert immunterapi resistens: Klinisk translasjon for personrettet medisin

Tildelt: kr 12,0 mill.

Kreft er nå den ledende dødsårsak i Norge. Selv om nye medisiner som aktiverer kroppens immunsystem (immunoterapi) har forbedret vår evne til å behandle kreft, får ikke de fleste pasienter vedvarende behandlingseffekt. De fleste krefttyper blir resistent mot terapi, sprer seg i kroppen og undergraver dagens terapi. Derfor er det viktig å forstå hvordan kreftceller utvikler kreftmedikament-resistens og unngår angrep fra immunsystemet. Vi studerer hvordan AXL-reseptoren driver terapiresistens i flere kreftformer ved å regulere tumor-immuncelle interaksjoner i tumoren. Vha nyere informatiske og cellebiologiske teknikker har vi identifisert nye AXL-reseptor former med unike egenskaper. En forbedret forståelse av AXL-reseptoren fra disse studiene kan bidra til forbedret kreftbehandling for pasienter.

Cancer is the leading cause of death in Norway and new treatment concepts are needed. Current cancer treatments such as immunotherapy do not afford lasting clinical benefit. Cancer cells invariably acquire therapy resistance and reemerge as advanced malignancy with increased mortality. Our research shows that cancer cells use the AXL receptor to resist therapy and evade the immune system. AXL is broadly associated with malignancy, drug resistance and poor patient survival and is a critical component of the tumor-immune interface: serving central roles in both tumor cells and immune cells that drive therapy failure. Supported by our recent results we seek to understand the molecular mechanism underpinning how AXL receptor signaling regulates tumor intrinsic resistance to immunotherapy. We address this through a state-of-the-art experimental approach comprising systems-level signal transduction analysis, AXL-targeting in combination with next generation iPS-T cell immunotherapy, and high dimensional single-cell mapping of phenotypic-spatial features of the tumor microenvironment in cancer patient biopsy samples. We will test the following hypotheses: (1) AXL receptor clusters have unique signal transduction characteristics that support therapy resistance; (2) AXL signaling complexes at the tumor-T cell immune synapse block T cell killing of cancer cells; (3) AXL targeting will improve adoptive T cell therapy; (4) AXL complexes at the tumor-T cell interface in cancer patient tumor biopsies will correlate with clinical outcome to immunotherapy. These insights will provide new understanding of a novel molecular mechanism underlying how how cancer evades immunotherapy and elucidate new precision medicine approaches that can address the knowledge gap in cancer treatment necessary to improve patient outcome.

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FRIMEDBIO-Fri prosj.st. med.,helse,biol

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