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

By D. DeNardo, J. Barreto, Pauline Andreu, L. Vasquez, D. Tawfik, Nikita S. Kolhatkar, Lisa M. Coussens. Cancer Cell, 2009

1,362 citations recorded by the source corpus.

Summary 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.

Subfields: Immunology, Oncology

View Paper: https://www.semanticscholar.org/paper/0b38b3fac6cdadd299bd400e944c0cceb5bccdee

How researchers see this paper

The researchers whose trusted networks rank it highest, strongest advocate first. Every researcher gets a different order.

In Immunology

1. A. Mantovani
2. Lisa M. Coussens
3. J. Pollard
4. P. Allavena
5. J. Joyce
6. B. Ruffell
7. F. Balkwill
8. Zena Werb

In Oncology

1. A. Mantovani
2. Lisa M. Coussens
3. J. Pollard
4. P. Allavena
5. J. Joyce
6. Zena Werb
7. F. Balkwill
8. B. Ruffell

Citations in the corpus

• Tumor Metastasis: Molecular Insights and Evolving Paradigms (2011, neutral): “Furthermore, stromal CD4+ T-lymphocytes promote mammary carcinoma invasion by stimulating tumorassociated macrophages (TAMs) to activate epidermal growth factor receptor (EGFR) signaling in the carcinoma cells (DeNardo et al., 2009).”
• Much More than M1 and M2 Macrophages, There are also CD169+ and TCR+ Macrophages (2015, methodology): “It has been described that TAM activation pathway enhances IRF3, STAT1, and the release of CCL2, CCL3, CCL5, IL-10, IL-12 (low), as well as other molecules such as PGE2 and epidermal growth factor (124, 125).”
• Targeting the ANG2/TIE2 axis inhibits tumor growth and metastasis by impairing angiogenesis and disabling rebounds of proangiogenic myeloid cells. (2011, background): “, 2005), and also stimulate tumor cell intravasation, dissemination, and metastasis (DeNardo et al., 2009; Qian and Pollard, 2010).”
• Cancer immunotherapy via dendritic cells (2012, neutral): “These cytokines prevent tumor cell apoptosis and promote the proliferation of cancer cells indirectly by stimulating tumor-associated macrophages to secrete EGF [87].”
• Leukocyte Complexity Predicts Breast Cancer Survival and Functionally Regulates Response to Chemotherapy (2011, background): “Malignant mammary epithelial cells from MMTV-PyMT mice express high levels of CSF1, which directly regulates TAM recruitment (and EGF expression) and induction of macrophage HIF1α (11, 38, 39).”
• Protective and pathogenic functions of macrophage subsets (2011, result): “These observations are also consistent with the tumour-promoting activities of IL-4 and IL-13, which also promote M2 macrophage differentiatio”
• Macrophage plasticity and polarization: in vivo veritas. (2012, neutral): “Th2 cells in skin (90, 91) and by antibody-producing B cells in breast carcinogenesis (92, 93).”