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T cells and monocyte-derived myeloid cells mediate immunotherapy-related hepatitis in a mouse model.
Llewellyn, Heather P; Arat, Seda; Gao, Jingjin; Wen, Ji; Xia, Shuhua; Kalabat, Dalia; Oziolor, Elias; Virgen-Slane, Richard; Affolter, Timothy; Ji, Changhua.
Afiliación
  • Llewellyn HP; Global Biomarkers, Drug Safety Research and Development (DSRD), La Jolla, CA, USA.
  • Arat S; Global Pathology and Investigative Toxicology, DSRD, Groton, CT, USA.
  • Gao J; Oncology Research Unit, Pfizer, La Jolla, CA, USA.
  • Wen J; Oncology Research Unit, Pfizer, La Jolla, CA, USA.
  • Xia S; Global Pathology and Investigative Toxicology, DSRD, Groton, CT, USA.
  • Kalabat D; Global Pathology and Investigative Toxicology, DSRD, Groton, CT, USA.
  • Oziolor E; Global Pathology and Investigative Toxicology, DSRD, Groton, CT, USA.
  • Virgen-Slane R; Global Biomarkers, Drug Safety Research and Development (DSRD), La Jolla, CA, USA.
  • Affolter T; Global Pathology, DSRD, Pfizer, La Jolla, CA, USA.
  • Ji C; Regulatory and Immunosafety Strategy, DSRD, Pfizer, La Jolla, CA, USA. Electronic address: changhua.ji2@pfizer.com.
J Hepatol ; 75(5): 1083-1095, 2021 11.
Article en En | MEDLINE | ID: mdl-34242700
BACKGROUND & AIMS: Immune checkpoint inhibitors (ICIs) are associated with immune-related adverse events (irAEs) which are more severe when ICIs are used in combination. We aimed to use a mouse model to elucidate the molecular mechanisms of immune-related hepatitis, one of the common irAEs associated with ICIs. METHODS: Immune phenotyping and molecular profiling were performed on Pdcd1-/- mice treated with anti-CTLA4 and/or the IDO1 inhibitor epacadostat or a 4-1BB agonistic antibody. RESULTS: ICI combination-induced hepatitis and 4-1BB agonist-mediated hepatitis share similar features yet maintain distinct immune signatures. Both were characterized by an expansion of periportal infiltrates and pan-zonal inflammation albeit with different morphologic characteristics. In both cases, infiltrates were predominantly CD4+ and CD8+ T cells with upregulated T-cell activation markers, ICOS and CD44. Depletion of CD8+ T cells abolished ICI-mediated hepatitis. Single-cell transcriptomics revealed that the hepatitis induced by combination ICIs is associated with a robust immune activation signature in all subtypes of T cells and T helper 1 skewing. Expression profiling revealed a central role for IFNγ and liver monocyte-derived macrophages in promoting a pro-inflammatory T-cell response to ICI combination and 4-1BB agonism. CONCLUSION: We developed a novel mouse model which offers significant value in yielding deeper mechanistic insight into immune-mediated liver toxicity associated with various immunotherapies. LAY SUMMARY: Hepatitis is one of the common immune-related adverse events in cancer patients receiving immune checkpoint inhibitor (ICI) therapy. The mechanisms of ICI-induced hepatitis are not well understood. In this paper, we identify key molecular mechanisms mediating immune intracellular crosstalk between liver T cells and macrophages in response to ICI in a mouse model.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Linfocitos T / Células Mieloides / Hepatitis Tipo de estudio: Prognostic_studies Límite: Animals Idioma: En Revista: J Hepatol Asunto de la revista: GASTROENTEROLOGIA Año: 2021 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Países Bajos
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Linfocitos T / Células Mieloides / Hepatitis Tipo de estudio: Prognostic_studies Límite: Animals Idioma: En Revista: J Hepatol Asunto de la revista: GASTROENTEROLOGIA Año: 2021 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Países Bajos