ABSTRACT
Chronically activated leukocytes recruited to premalignant tissues functionally contribute to cancer development; however, mechanisms underlying pro- versus anti-tumor programming of neoplastic tissues by immune cells remain obscure. Using the K14-HPV16 mouse model of squamous carcinogenesis, we report that B cells and humoral immunity foster cancer development by activating Fcgamma receptors (FcgammaRs) on resident and recruited myeloid cells. Stromal accumulation of autoantibodies in premalignant skin, through their interaction with activating FcgammaRs, regulate recruitment, composition, and bioeffector functions of leukocytes in neoplastic tissue, which in turn promote neoplastic progression and subsequent carcinoma development. These findings support a model in which B cells, humoral immunity, and activating FcgammaRs are required for establishing chronic inflammatory programs that promote de novo carcinogenesis.
Subject(s)
B-Lymphocytes/immunology , Carcinoma, Squamous Cell/immunology , Neoplasms, Glandular and Epithelial/immunology , Receptors, IgG/physiology , Animals , B-Lymphocytes/metabolism , CD11b Antigen/metabolism , Carcinoma, Squamous Cell/blood supply , Carcinoma, Squamous Cell/metabolism , Carcinoma, Squamous Cell/pathology , Immunity, Humoral/physiology , Mast Cells/immunology , Mast Cells/metabolism , Mast Cells/pathology , Mice , Mice, Transgenic , Models, Biological , Myeloid Cells/immunology , Myeloid Cells/metabolism , Neoplasms, Glandular and Epithelial/blood supply , Neoplasms, Glandular and Epithelial/metabolism , Neoplasms, Glandular and Epithelial/pathology , Neovascularization, Pathologic , Receptors, IgG/metabolismABSTRACT
During breast cancer development, increased presence of leukocytes in neoplastic stroma parallels disease progression; however, the functional significance of leukocytes in regulating protumor versus antitumor immunity in the breast remains poorly understood. Utilizing the MMTV-PyMT model of mammary carcinogenesis, we demonstrate that IL-4-expressing CD4(+) T lymphocytes indirectly promote invasion and subsequent metastasis of mammary adenocarcinomas by directly regulating the phenotype and effector function of tumor-associated CD11b(+)Gr1(-)F4/80(+) macrophages that in turn enhance metastasis through activation of epidermal growth factor receptor signaling in malignant mammary epithelial cells. Together, these data indicate that antitumor acquired immune programs can be usurped in protumor microenvironments and instead promote malignancy by engaging cellular components of the innate immune system functionally involved in regulating epithelial cell behavior.
