Dataset Information

Graft-Versus-Tumor Effect in Major Histocompatibility Complex-Mismatched Mouse Liver Transplantation.

ABSTRACT: Liver transplantation (LT) is currently considered an important method in treating hepatocellular carcinoma (HCC) and an alternative treatment for other liver malignancies. Here, we demonstrated that the graft-versus-tumor (GVT) effect exists in allogeneic liver transplantation (allo LT). Recipient-derived T cells played a critical role in the GVT process of allo LT, as demonstrated by extensive infiltration and significant activation of recipient T cells in the tumor after surgery. Moreover, this process was related to donor-derived T/B cells by improving the immune microenvironment in the tumor, as demonstrated by elevated levels of interferon-γ (IFN-γ), tumor necrosis factor-α (TNF-α), interleukin-2 (IL-2), IL-6, IL-16, chemokine (C-X-C motif) ligand 10 (CXCL10), and CXCL11 and decreased levels of IL-10 and IL-4 at tumor sites. Additionally, tacrolimus (FK506) treatment inhibited the GVT effect on allo LT. Donor liver-derived T/B cells infiltrate extrahepatic tumors to trigger a strong T-cell-mediated immune response and thus improve the tumor immune microenvironment.

SUBMITTER: Yu D

PROVIDER: S-EPMC6771797 | biostudies-other | 2019 Aug

REPOSITORIES: biostudies-other

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Graft-Versus-Tumor Effect in Major Histocompatibility Complex-Mismatched Mouse Liver Transplantation.

Yu Dongdong D Wang Lidong L Wu Tianchun T Zhang Yaohui Y Tian Yang Y Wang Yan Y Cui Chenwei C Li Hui H Zhang Jinhua J Zhou Lin L Yan Sheng S Zheng Shusen S

Liver transplantation : official publication of the American Association for the Study of Liver Diseases and the International Liver Transplantation Society 20190709 8

Liver transplantation (LT) is currently considered an important method in treating hepatocellular carcinoma (HCC) and an alternative treatment for other liver malignancies. Here, we demonstrated that the graft-versus-tumor (GVT) effect exists in allogeneic liver transplantation (allo LT). Recipient-derived T cells played a critical role in the GVT process of allo LT, as demonstrated by extensive infiltration and significant activation of recipient T cells in the tumor after surgery. Moreover, th ...[more]

PMID: 31152624

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Project description:BackgroundAllogeneic bone marrow transplantation (allo-BMT) is a potentially curative therapy for a variety of hematologic diseases, but benefits, including graft-versus-tumor (GVT) activity are limited by graft-versus-host-disease (GVHD). Carcinoembryonic antigen related cell adhesion molecule 1 (Ceacam1) is a transmembrane glycoprotein found on epithelium, T cells, and many tumors. It regulates a variety of physiologic and pathological processes such as tumor biology, leukocyte activation, and energy homeostasis. Previous studies suggest that Ceacam1 negatively regulates inflammation in inflammatory bowel disease models.MethodsWe studied Ceacam1 as a regulator of GVHD and GVT after allogeneic bone marrow transplantation (allo-BMT) in mouse models. In vivo, Ceacam1(-/-) T cells caused increased GVHD mortality and GVHD of the colon, and greater numbers of donor T cells were positive for activation markers (CD25(hi), CD62L(lo)). Additionally, Ceacam1(-/-) CD8 T cells had greater expression of the gut-trafficking integrin ?(4)?(7), though both CD4 and CD8 T cells were found increased numbers in the gut post-transplant. Ceacam1(-/-) recipients also experienced increased GVHD mortality and GVHD of the colon, and alloreactive T cells displayed increased activation. Additionally, Ceacam1(-/-) mice had increased mortality and decreased numbers of regenerating small intestinal crypts upon radiation exposure. Conversely, Ceacam1-overexpressing T cells caused attenuated target-organ and systemic GVHD, which correlated with decreased donor T cell numbers in target tissues, and mortality. Finally, graft-versus-tumor survival in a Ceacam1(+) lymphoma model was improved in animals receiving Ceacam1(-/-) vs. control T cells.ConclusionsWe conclude that Ceacam1 regulates T cell activation, GVHD target organ damage, and numbers of donor T cells in lymphoid organs and GVHD target tissues. In recipients of allo-BMT, Ceacam1 may also regulate tissue radiosensitivity. Because of its expression on both the donor graft and host tissues, this suggests that targeting Ceacam1 may represent a potent strategy for the regulation of GVHD and GVT after allogeneic transplantation.

Dataset Information

Graft-Versus-Tumor Effect in Major Histocompatibility Complex-Mismatched Mouse Liver Transplantation.

Publications

Graft-Versus-Tumor Effect in Major Histocompatibility Complex-Mismatched Mouse Liver Transplantation.

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