Given the close interaction between tumor cells and stromal cells in the tumor microenvironment (TME), TME-targeted strategies would be promising for developing integrated cancer immunotherapy. Cancer-associated fibroblasts (CAFs) are the dominant stromal component, playing critical roles in generation of the pro-tumorigenic TME. We focused on the immunosuppressive trait of CAFs, and systematically explored the alteration of tumor-associated immune responses by CAF-targeted therapy. C57BL/6 mice s.c. bearing syngeneic E.G7 lymphoma, LLC1 Lewis lung cancer, or B16F1 melanoma were treated with an anti-fibrotic agent, tranilast, to inhibit CAF function. The infiltration of immune suppressor cell types, including regulatory T cells and myeloid-derived suppressor cells, in the TME was effectively decreased through reduction of stromal cell-derived factor-1, prostaglandin E2, and transforming growth factor-β. In tumor-draining lymph nodes, these immune suppressor cell types were significantly decreased, leading to activation of tumor-associated antigen-specific CD8+ T cells. In addition, CAF-targeted therapy synergistically enhanced multiple types of systemic antitumor immune responses such as the cytotoxic CD8+ T cell response, natural killer activity, and antitumor humoral immunity in combination with dendritic cell-based vaccines; however, the suppressive effect on tumor growth was not observed in tumor-bearing SCID mice. These data indicate that systemic antitumor immune responses by various immunologic cell types are required to bring out the efficacy of CAF-targeted therapy, and these effects are enhanced when combined with effector-stimulatory immunotherapy such as dendritic cell-based vaccines. Our mouse model provides a novel rationale with TME-targeted strategy for the development of cell-based cancer immunotherapy.
IgG4-related sclerosing disease can occur in the cardiovascular system and some inflammatory abdominal aortic aneurysms have been shown to belong to IgG4-related sclerosing disease. Herein is reported a case of IgG4-related inflammatory aortic aneurysm of the aortic arch. A 71-year-old Japanese man was found to have an aneurysm of the aortic arch with maximum dimension of 5.5 cm. The surgically resected aneurysm wall had conspicuous fibrosclerotic changes, dense lymphoplasmacytic infiltration and occasional obliterative phlebitis in the adventitia; the thickness of the adventitia was 6.5 mm. Immunohistochemistry indicated numerous IgG4-positive plasma cell infiltrates; 84% of the IgG-bearing cells were IgG4 positive. The diagnosis of IgG4-related inflammatory aortic aneurysm of the aortic arch was made. Although previously reported IgG4-related inflammatory aortic aneurysms were confined to the abdominal aorta, the present case report demonstrates that IgG4-related inflammatory aortic aneurysm can occur in the aortic arch, thereby extending the spectrum of IgG4-related periaortitis. Further studies are needed to clarify the spectrum of IgG4-related sclerosing disease in the cardiovascular system.
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