Origins of tumor-associated macrophages and neutrophils

By V. Cortez-Retamozo, Martin Etzrodt, Andita Newton, P. Rauch, A. Chudnovskiy, Cedric Berger, R. Ryan, Y. Iwamoto, Brett Marinelli, Rostic Gorbatov and 10 more. Proceedings of the National Academy of Sciences of the United States of America, 2012

658 citations recorded by the source corpus.

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-6Chi monocytic and CD11b+ Ly-6Ghi 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.

Subfields: Immunology, Oncology

View Paper: https://www.semanticscholar.org/paper/16381881dddc841a6d25379f1c81ea39d0378543

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In Immunology

1. Guido Kroemer
2. L. Zitvogel
3. M. Pittet
4. R. Noy
5. P. Murray
6. A. Mildner
7. Jong-Sup Bae
8. Jaehong Kim

In Oncology

1. Guido Kroemer
2. R. Noy
3. Jong-Sup Bae
4. Jaehong Kim
5. M. Pittet
6. L. Zitvogel
7. D. Gabrilovich
8. P. Murray

Citations in the corpus

• Immunogenic chemotherapy sensitizes tumors to checkpoint blockade therapy (2016, neutral): “(C) Lung weight as proxy for tumor burden (Cortez-Retamozo et al., 2012) measured on day 44 in mice bearing orthotopic KP1.”
• Macrophage Polarization. (2017, background): “Once inside tumors, the process of development from Ly6C+ cells to mature macrophages is dynamic, in that cells are dying and replaced by new monocytes as the tumor grows and undergoes hypoxia and remodeling (16, 17, 20).”
• Tumor-Associated Macrophages and Neutrophils in Tumor Microenvironment (2016, background): “In the transition from benign to malignant invasive cancer, the TME is flooded with cytokines and growth factors.”
• Imaging macrophages with nanoparticles. (2014, methodology): “Imaging TAMs could thus be used to (1) provide prognostic information, (2) visualize differences in TAM concentrations within a single tumour or across metastases, (3) guide biopsies, (4) define tumour margins101,119 and (5) quantitate responses to treatment by mapping apoptosis-initiated macrophage”
• Tumor-associated macrophages: from mechanisms to therapy (2014, background): “probably because the immune system has access to the products of mutated genes and/or recognizes tissue damage caused by invasion (Coussens and Pollard, 2011; Gajewski et al., 2013).”
• The intestinal microbiota modulates the anticancer immune effects of cyclophosphamide (2013, background): “Using a transgenic tumor model of autochthonous lung carcinogenesis driven by oncogenic K-Ras coupled to conditional p53 deletion (20), we confirmed the inhibitory role of vancomycin on the anticancer efficacy of a CTX-based chemotherapeutic regimen (Fig.”
• Developmental and Functional Heterogeneity of Monocytes. (2018, background): “Monocytic MDSC are derive from circulating Ly6CHi monocytes, either directly from the BM or from the splenic peripheral reservoir in a CCR2-dependent manner (Cortez-Retamozo et al., 2012; Shand et al., 2014).”
• The nature of myeloid-derived suppressor cells in the tumor microenvironment (2016, background): “Recently, the spleen was reported to be the reservoir of Ly6C monocytes that can migrate to tumors and differentiate into TAM [76].”