Tumor Progression Stage and Anatomical Site Regulate Tumor-Associated Macrophage and Bone Marrow-Derived Monocyte Polarization

摘要

Tumor-associated macrophages (TAMs) encourage and coordinate neoplastic growth. In late stage human lung adenocarcinoma, TAMs exhibited mixed M1 (classical; argI^lowiNOS^high) and M2 (alternative; argI^highiNOS^low) polarization based on arginine metabolism. In several murine cancer models including chemically and genetically-induced primary lung tumors, prostate tumors, colon xenografts, and lung metastases, TAMs expressed argI^highiNOS^low early during tumor formation; argI^lowiNOS^high polarization also occurred during malignancy in some models. In a chemically-induced lung tumor model, macrophages expressed argI^highiNOS^low within one week after carcinogen treatment, followed by similar polarization of bone marrow–derived monocytes (BDMCs) a few days later. TAMs surrounding murine prostate tumors also expressed argI^highiNOS^low early during tumorigenesis, indicating that this polarization is not unique to neoplastic lungs. In a human colon cancer xenograft model, the primary tumor was surrounded by argI^highiNOS^low-expressing TAMs, and BDMCs also expressed argI^highiNOS^low, but pulmonary macrophages adopted argI^highiNOS^low polarization only after tumors metastasized to the lungs. Persistence of tumors is required to maintain TAM polarization. Indeed, in both conditional mutant >Kras- and >FGF10-driven models of lung cancer, mice expressing the transgene develop lung tumors that regress rapidly when the transgene is silenced. Furthermore, pulmonary macrophages expressed argI^highiNOS^low on tumor induction, but then returned to argI^low iNOS^low (no polarization) after tumors regressed. Manipulating TAM function or depleting TAMs may provide novel therapeutic strategies for preventing and treating many types of cancer.