Origins of tumor-associated macrophages and neutrophils

Abstract

Tumor-associated macrophages (TAMs) and tumor-associated neutrophils (TANs) can control cancer growth and exist in almost all solid neoplasms. The cells are known to descend from immature monocytic and granulocytic cells, respectively, which are produced in the bone marrow. However, the spleen is also a recently identified reservoir of monocytes, which can play a significant role in the inflammatory response that follows acute injury. Here, we evaluated the role of the splenic reservoir in a genetic mouse model of lung adenocarcinoma driven by activation of oncogenic Kras and inactivation of p53. We found that high numbers of TAM and TAN precursors physically relocated from the spleen to the tumor stroma, and that recruitment of tumor-promoting spleen-derived TAMs required signaling of the chemokine receptor CCR2. Also, removal of the spleen, either before or after tumor initiation, reduced TAM and TAN responses significantly and delayed tumor growth. The mechanism by which the spleen was able to maintain its reservoir capacity throughout tumor progression involved, in part, local accumulation in the splenic red pulp of typically rare extramedullary hematopoietic stem and progenitor cells, notably granulocyte and macrophage progenitors, which produced CD11b + Ly-6C hi monocytic and CD11b + Ly-6G hi granulocytic cells locally. Splenic granulocyte and macrophage progenitors and their descendants were likewise identified in clinical specimens. The present study sheds light on the origins of TAMs and TANs, and positions the spleen as an important extramedullary site, which can continuously supply growing tumors with these cells.

Invasive breast cancer reprograms early myeloid differentiation in the bone marrow to generate immunosuppressive neutrophils

“…Expansion of T cell-suppressive myeloid cells in cancer is associated with enlargement of the spleen (29), which may act as a reservoir for extramedullary hematopoiesis (30). We also observed an enlarged spleen in late-stage PyMT mice (Fig.…”

SIV Encephalitis Lesions Are Composed of CD163+ Macrophages Present in the Central Nervous System during Early SIV Infection and SIV-Positive Macrophages Recruited Terminally with AIDS

“…86e88 A splenic reservoir of monocytes has been identified in mice, which is mobilized in response to myocardial infarction and lung adenocarcinoma. 89,90 Alternatively, emerging studies support the notion of parenchymal macrophage repopulation in tissues and not from bone marrow, which is an interesting field of future study that may, in part, account for a lack of BrdU þ CD163 macrophages in parenchymal lesions in our study. 91,92 The Presence of CD163 þ BrdU þ Macrophages in the Meninges and Choroid Plexus Underscores Differences between CNS Compartments and a Possible Route of Viral Entry into the CNS Given that we did not observe CD163 þ BrdU þ macrophages in the perivascular space and SIVE lesions, it is interesting that we observed CD163 þ BrdU þ macrophages in the meninges and choroid plexus in numbers equal to or greater than MAC387 þ BrdU þ macrophages.…”

Monocytes and Macrophages in Cancer: Development and Functions

“…Recently, Pittet and colleagues revealed alterations in myeloid development in a model of lung adenocarcinoma driven by activation of K-Ras and inactivation of p53 [10]. In this model, early hematopoietic progenitors (such as the GMP) relocated to the spleen during tumor progression and locally produced monocytes and granulocytes that contributed to tumor growth.…”

“…Still, monocytes are also produced by extra-medullary hematopoiesis in the spleen and increase under inflammatory conditions such as atherosclerosis and cancer as recently shown [9,10]. In the bone marrow, monocytes are generated from HSC in a sequential process of differentiation and commitment steps [3,11], collectively called monopoiesis (Fig.…”