Mucosal-associated invariant T cells in Hepatocellular Carcinoma
Final Report Abstract
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.
Publications
- "Hydroxychloroquine Can Impair Tumor Response to Anti-Pd1 in Subcutaneous Mouse Models." iScience 24, no. 1 (2021): 101990
Wabitsch, S., J.C. McVey, C. Ma, B. Ruf, O. Kamenyeva, J.D. McCallen, L.P. Diggs, B. Heinrich, and T.F. Greten
(See online at https://doi.org/10.1016/j.isci.2020.101990) - “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, S., T. Mayank, B. Benjamin, Z. Qianfei, J.D. McCallen, J.C. McVey, M. Chi, B.L. Green, L.P. Diggs, B. Heinrich, T.F. Greten
(See online at https://doi.org/10.1016/j.jcmgh.2021.05.011) - Metformin treatment rescues CD8+ T cell response to immune checkpoint inhibitor therapy in mice with NAFLD. J Hepatol. 2022
Wabitsch S., J.D. McCallen, O. Kamenyeva, B. Ruf, J.C. McVey, J. Kabat, J.S Walz, Y. Rotman, K.C. Bauer, A.J. Craig, M. Pouzolles, I. Phadke, V. Catania, B.L. Green, C. Fu, L.P. Diggs, B. Heinrich, X.W. Wang, C. Ma, T.F. Greten
(See online at https://doi.org.10.1016/j.jhep.2022.03.010)
