Mukosa-assoziierte invariante T-Zellen im Hepatozellulären Karzinom
Zusammenfassung der Projektergebnisse
The initial research plan focused on exploring the immune landscape of HCC and MAIT cells in HCC. Due to the COVID-19 pandemic we changed the focus of the research plan on the influences of ICI therapy. Starting with a COVID-19 related project, two further projects were established with the overall question which patient or medication dependent circumstances influence the response to ICI therapy. We used well-annoted murine tumor modes as well as comprehensive immunophenotyping via multiplex immunostaining and sequencing to refine our understanding of T cell response to ICI therapy. We were also able to show CD8+ T cell mobility at the border and core of HCC in vivo for the first time. Additionally, using sorted hepatic CD8+ T cells for mobility experiments ex vivo allowed us to investigate if changes of CD8+ T cells is dependent on the hepatic and intra-tumoral environment or an CD8+ T cell intrinsic effect. With these results we were able to establish a combination therapy for iCC using trametinib+anti-PD-1 as well as metformin+ICI therapy for HCC in NASH. These findings have implications for clinical practice: as a potential treatment strategy for iCC as well as a new combination therapy for NASH patients with HCC.
Projektbezogene Publikationen (Auswahl)
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"Hydroxychloroquine Can Impair Tumor Response to Anti-Pd1 in Subcutaneous Mouse Models." iScience 24, no. 1 (2021): 101990
Wabitsch, Simon; McVey, John C.; Ma, Chi; Ruf, Benjamin; Kamenyeva, Olena; McCallen, Justin D.; Diggs, Laurence P.; Heinrich, Bernd & Greten, Tim F.
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“Anti–PD-1 in Combination With Trametinib Suppresses Tumor Growth and Improves Survival of Intrahepatic Cholangiocarcinoma in Mice” Cellular and Molecular Gastroenterology and Hepatology, Volume 12, Issue 3, 1166 – 1178
Wabitsch, Simon; Tandon, Mayank; Ruf, Benjamin; Zhang, Qianfei; McCallen, Justin D.; McVey, John C.; Ma, Chi; Green, Benjamin L.; Diggs, Laurence P.; Heinrich, Bernd & Greten, Tim F.
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Metformin treatment rescues CD8+ T cell response to immune checkpoint inhibitor therapy in mice with NAFLD. J Hepatol. 2022
Wabitsch, Simon; McCallen, Justin D.; Kamenyeva, Olena; Ruf, Benjamin; McVey, John C.; Kabat, Juraj; Walz, Juliane S.; Rotman, Yaron; Bauer, Kylynda C.; Craig, Amanda J.; Pouzolles, Marie; Phadke, Ira; Catania, Vanessa; Green, Benjamin L.; Fu, Claude; Diggs, Laurence P.; Heinrich, Bernd; Wang, Xin Wei; Ma, Chi; ... & Greten, Tim F.
