Targeting Tissue-Resident Macrophages and Their Progenitors to Suppress Cancer Progression
Paulina Pathria1, Hideyuki Takahashi1, Judith Varner2 1Moores Cancer Center and 2Department of Pathology, University of California, San Diego, CA, USA
Macrophages play a key role in promoting tumor growth and resistance to therapy. Tissue resident as well as bone marrow derived macrophages play critical roles in promoting tumor growth. Tissue-resident macrophages were recently shown to originate in the yolk sac or fetal liver during embryogenesis; these cells self-maintain in post-natal tissues independent of hematopoietic stem cells. Tissue resident macrophages and bone marrow derived macrophages both rapidly accumulate in tumors where they play independent roles in promoting tumor growth. Tissue resident macrophages are CD11b+Gr1-F4/80hiCX3CR1hiCCR2-Ki67+ cells that accumulate in tumors independently of trafficking receptors. In contrast, bone marrow derived CD11b+Gr1+F4/80loCX3CR1loCCR2+ macrophages accumulate in tumors in an integrin α4β1/αLβ1 and CCR2 or CXCR4-dependent manner. Gene expression studies show that tumor associated tissue resident macrophages are highly proliferative, immune suppressive myeloid cells that are less proangiogenic than bone marrow derived macrophages. Our studies show that tumor cells induce the expansion of tissue resident macrophage progenitor cells by secreting cytokines that induce macrophage proliferation in tumors. Notably, tumor growth and colony-forming activity are significantly inhibited in mice treated with inhibitors of myeloid progenitors. Tumor growth can also be suppressed with inhibitors of macrophage polarization such as PI3Kgamma inhibitors. The combination of these therapeutic approaches synergistically suppressed tumor growth. In addition, tumors adoptively transferred with tissue resident macrophage progenitor cells exhibited a significant growth advantage over control tumors. Our studies show that tissue resident macrophage progenitors promote aggressive tumor growth that can be suppressed by inhibition of their proliferation.
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