It is well established that chronic inflammation contributes to cancer development. Many studies have demonstrated that inflammatory leukocytes promote epithelial cancer by providing soluble growth and survival factors to initiated cells and contribute to tissue remodeling and angiogenesis via synthesis of extracellular proteases;thus, physiological processes necessary for tumor development, e.g., enhanced cell survival, tissue remodeling and angiogenesis, are regulated by leukocytes and the soluble mediators they deliver. However, molecular mechanisms responsible for initiation and/or maintenance of chronic inflammatory pathways that potentiate growth of developing neoplasms are not well understood. We have previously reported a provocative role for adaptive immune cells as regulators of inflammation-associated epithelial cancer development. Using the HPV16 transgenic mouse model of squamous carcinoma development, we found that genetic deletion of adaptive B and T lymphocytes resulted in attenuated recruitment of innate immune cells towards premalignant skin. As a consequence, tissue remodeling, angiogenesis and epithelial hyperproliferation were significantly attenuated, culminating in reduced carcinoma incidence. Importantly, transfer of B220+CD19+ B cells or serum from HPV16 mice into T and B lymphocyte-deficient/HPV16 mice resulted in restored characteristics of premalignancy, e.g., immunoglobulin deposition in neoplastic skin, recruitment of innate leukocytes, activation of angiogenic vasculature and keratinocyte hyperproliferation. Together, these data support the hypothesis that peripheral B cell activation is an essential step for early epithelial neoplasia and B cell-derived soluble mediators are necessary for establishing chronic inflammatory states that potentiate malignant progression. Based on this hypothesis, the overall goal of this application is to examine whether specific targeting of B lymphocytes or instead, specific targeting of B lymphocyte effector pathways represent viable therapeutic targets for anti-cancer therapy. To assess this, we propose to: 1) Determine the parameters of neoplastic progression in HPV16 mice that are B lymphocyte-dependent;2) Determine what parameters of neoplastic progression in HPV16 mice are FcR?-dependent;3) Define functionally significant myeloid cell types regulated by humoral immunity that potentiate carcinogenesis. PROJECT NARRATIVE: The major goal of our project is to examine whether specific targeting of B lymphocytes, or instead, specific targeting of B lymphocyte effector pathways represent viable therapeutic strategies for attenuating chronic inflammation associated with epithelial cancer development. Identification of regulatory cells/molecules/pathways essential for either initiating or maintaining chronic inflammation associated with epithelial neoplasms, would provide valuable anti-cancer therapeutic targets with which to combat growth and progression of solid tumors.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project (R01)
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Tumor Microenvironment Study Section (TME)
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Howcroft, Thomas K
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Oregon Health and Science University
Anatomy/Cell Biology
Schools of Medicine
United States
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Ruffell, Brian; Chang-Strachan, Debbie; Chan, Vivien et al. (2014) Macrophage IL-10 blocks CD8+ T cell-dependent responses to chemotherapy by suppressing IL-12 expression in intratumoral dendritic cells. Cancer Cell 26:623-37
Affara, Nesrine I; Ruffell, Brian; Medler, Terry R et al. (2014) B cells regulate macrophage phenotype and response to chemotherapy in squamous carcinomas. Cancer Cell 25:809-21
Medler, Terry R; Coussens, Lisa M (2014) Duality of the immune response in cancer: lessons learned from skin. J Invest Dermatol 134:E23-8
Anand, Sudarshan; Coussens, Lisa M (2014) Manipulating microRNAs to regulate macrophage polarization in gliomas. J Natl Cancer Inst 106:
Ruffell, Brian; Affara, Nesrine I; Cottone, Lucia et al. (2013) Cathepsin C is a tissue-specific regulator of squamous carcinogenesis. Genes Dev 27:2086-98
Ganesan, Anusha-Preethi; Johansson, Magnus; Ruffell, Brian et al. (2013) Tumor-infiltrating regulatory T cells inhibit endogenous cytotoxic T cell responses to lung adenocarcinoma. J Immunol 191:2009-17
Gunderson, Andrew J; Coussens, Lisa M (2013) B cells and their mediators as targets for therapy in solid tumors. Exp Cell Res 319:1644-9
Palucka, Karolina; Coussens, Lisa M; O'Shaughnessy, Joyce (2013) Dendritic cells, inflammation, and breast cancer. Cancer J 19:511-6
Ruffell, Brian; Affara, Nesrine I; Coussens, Lisa M (2012) Differential macrophage programming in the tumor microenvironment. Trends Immunol 33:119-26
Ruffell, Brian; Au, Alfred; Rugo, Hope S et al. (2012) Leukocyte composition of human breast cancer. Proc Natl Acad Sci U S A 109:2796-801

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