Abstract SY31-02: Macrophages–evildoers in cancer
Authors: Pollard Jeffrey W. 
Published: July 2017

Tumor evolution to malignancy requires manipulation of its tissue microenvironment to be promoting. This is particularly true for the immune infiltrate that is biased away from responding to the tumor to effect control and instead actively promotes progression. The tumor immune response thus downregulates cytotoxic T-cell responses and promotes tissue repair and morphogenic activities of the infiltrating immune cells (1). Thus the environment tends to be dominated by innate immune cells, particularly macrophages and neutrophils, while cytotoxic T cells are often excluded. Our interest has been in macrophages as these, in many different mouse models of cancer, promote tumor progression and enhance metastasis. In fact, macrophages appear to be involved in every step of tumor progression. They stimulate tumor initiation, enhance angiogenesis, promote tumor cell migration and intravasation, increase stem cell viability, suppress immune responses, and, at the metastatic site, promote extravasation and persistent growth. Consequently, macrophage ablation results in inhibition of tumor progression and metastasis (2). These macrophage biologic activities are induced through a dynamic interplay with tumor cells that often involves reciprocal signaling. We have been particularly interested in the involvement of macrophages in enhancing metastasis since it is metastatic disease that is responsible for most cancer deaths. We have demonstrated a chemokine-signaling cascade that results in the recruitment of the progenitor monocytes and their retention in the tissue (3, 4). This results in differentiation of what we have termed metastasis-associated macrophages (MAMs) that confer survival signals and growth advantage to metastatic cells. These MAMs in term respond to local signals to upregulate an inflammatory gene signature through the tyrosine kinase transmembrane receptors, vascular endothelial growth factor receptor 1 (VEGFR1 or FLT1) and colony stimulating factor 1 receptor (CSF1R) (5). Furthermore, monocytes appear to be preadapted by the primary tumor to promote metastasis by the generation of preferred sites know as premetastatic niches (6). Thus, understanding monocyte biology, the mechanisms of their recruitment, and differentiation is of central importance to the fundamental appreciation of the role of macrophages in the tumor. My talk will focus on these questions.

References

1. Ruffell B, DeNardo DG, Affara NI, Coussens LM. Lymphocytes in cancer development: polarization towards pro-tumor immunity. Cytokine Growth Factor Rev 2010;21(1):3-10.

2. Kitamura T, Qian BZ, Pollard JW. Immune cell promotion of metastasis. Nat Rev Immunol 2015;15(2):73-86.

3. Qian BZ, Li J, Zhang H, Kitamura T, Zhang J, Campion LR, et al. CCL2 recruits inflammatory monocytes to facilitate breast-tumour metastasis. Nature 2011;475(7355):222-5.

4. Kitamura T, Qian BZ, Soong D, Cassetta L, Noy R, Sugano G, et al. CCL2-induced chemokine cascade promotes breast cancer metastasis by enhancing retention of metastasis-associated macrophages. J Exp Med 2015;212(7):1043-59.

5. Qian BZ, Zhang H, Li J, He T, Yeo EJ, Soong DY, et al. FLT1 signaling in metastasis-associated macrophages activates an inflammatory signature that promotes breast cancer metastasis. J Exp Med 2015;212(9):1433-48.

6. Peinado H, Aleckovic M, Lavotshkin S, Matei I, Costa-Silva B, Moreno-Bueno G, et al. Melanoma exosomes educate bone marrow progenitor cells toward a pro-metastatic phenotype through MET. Nat Med 2012;18(6):883-91.

Citation Format: Jeffrey W. Pollard. Macrophages–evildoers in cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr SY31-02. doi:10.1158/1538-7445.AM2017-SY31-02