CD4+ T Cells Regulate Pulmonary Metastasis of Mammary Carcinomas by Enhancing Protumor Properties of Macrophages

Department of Pathology, University of California, San Francisco, CA 94143, USA.
Cancer cell (Impact Factor: 23.52). 09/2009; 16(2):91-102. DOI: 10.1016/j.ccr.2009.06.018
Source: PubMed


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.

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    • "In contrast, breast tumor models are characterized by a Th2 bias (Czarneski et al., 2001; Jensen et al., 2003). Our observation of increased branching in Th2-organoid co-cultures echoes the observation of Th2 cells dominating mammary adenocarcinomas and promoting invasion as well as pulmonary metastasis (DeNardo et al., 2009). In fact, numerous findings in cancer research imply that survival and differentiation of mammary epithelial cells that form tumors are indeed regulated by a delicate balance between Th1/Th2 signaling. "
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    Developmental Cell 08/2015; 34(5). DOI:10.1016/j.devcel.2015.07.015 · 9.71 Impact Factor
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    • "Please cite this article in press as: Mohd W. Nasser, Mohamad Elbaz, Dinesh K. Ahirwar, Ramesh K. Ganju, Conditioning solid tumor microenvironment through inflammatory chemokines and S100 family proteins, Cancer Letters (2015), doi: 10.1016/j.canlet.2015.05.002 shown a strong association between TAMs' density and poor prognosis in several cancer types [95] [96] [97]. TAMs are macrophages with the M2 phenotype that are activated primarily by interleukin-4 (IL- 4) produced by CD4 + T cells [98]. M1 are macrophages that have anti-tumorigenic potential, whereas M2 is another type, mainly converted from M1 subtype and has pro-tumorigenic ability [96] [99]. "
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    ABSTRACT: Recently, there has been growing attention to the role of the tumor microenvironment (TME) in cancer growth, metastasis and emergence of chemotherapy resistance. Stromal and tumor cells make up the TME and interact with each other through a complex cross-talk manner. This interaction is facilitated by a variety of growth factors, cytokines, chemokines and S100 proteins. In this review, we focus on chemokines and their cognate receptors in regulating the tumorigenic process. Chemokines are cytokines that have chemotactic potential. Chemokine receptors are expressed on tumor cells and stromal cells. Chemokines and their cognate receptors modulate tumor growth and metastasis in a paracrine and autocrine manner. They play a major role in the modulation of stromal cell recruitment, angiogenic potential, cancer cell proliferation, survival, adhesion, invasion and metastasis to distant sites. In addition, a new class of calcium binding family S100 proteins has getting attention as they play significant roles in tumor progression and metastasis by modulating TME. Here, we highlight recent developments regarding the inflammatory chemokine/S100 proteins systems in the TME. We also focus on how chemokines/S100 proteins, through their role in the TME, modulate cancer cell ability to grow, proliferate, invade and metastasize to different organs. This review highlights the possibility of using the chemokine/chemokine receptor axis as a promising strategy in cancer therapy, the current difficulties in achieving this goal, and how it could be overcome for successful future therapeutic intervention. Copyright © 2015. Published by Elsevier Ireland Ltd.
    Cancer letters 05/2015; 365(1). DOI:10.1016/j.canlet.2015.05.002 · 5.62 Impact Factor
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    • "In this study, we identified a Th2 biased gene expression of the intratumoral CD4+ T cells, which has previously been shown to suppress the anti-tumor immunity of the host [10] [11] [12] [33]. By integrating the DE genes of the intratumoral CD4+ T cells (CD4 DEGs) with the DE genes of the bulk BC tissues (BC DEGs), we identified five dysregulated cytokines as the predictor to reflect the Th2 polarization of the intratumoral CD4+ T cells, which in turn could be used to predict the immune-polarization side effects of tamoxifen treatment. "
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