Abstract
Tumor-associated macrophages (TAMs) play a central role in tumor progression, metastasis, and recurrence after treatment. Macrophage plasticity and diversity allow their classification along a M1–M2 polarization axis. Tumor-associated macrophages usually display a M2-like phenotype, associated with pro-tumoral features whereas M1 macrophages exert antitumor functions. Targeting the reprogramming of TAMs toward M1-like macrophages would thus be an efficient way to promote tumor regression. This can be achieved through therapies including chemotherapy, immunotherapy, and radiotherapy (RT). In this review, we first describe how chemo- and immunotherapies can target TAMs and, second, we detail how RT modifies macrophage phenotype and present the molecular pathways that may be involved. The identification of irradiation dose inducing macrophage reprogramming and of the underlying mechanisms could lead to the design of novel therapeutic strategies and improve synergy in combined treatments.
Highlights
In 1863, Rudolf Virchow was the first to highlight the infiltration of leukocytes in tumor, thereby proposing a link between inflammation and tumorigenesis
TUMOR-ASSOCIATED MACROPHAGES (TAMs) reprogramming is induced through various mechanisms
nuclear factor kappa B (NFκB) pathway seems to be a central target for macrophage reprogramming
Summary
In 1863, Rudolf Virchow was the first to highlight the infiltration of leukocytes in tumor, thereby proposing a link between inflammation and tumorigenesis. High doses of X-rays (25 Gy in one shot or 60 Gy fractioned over 3 weeks) increased the number of M2-like TAMs in a murine model of prostate cancer (TRAMP-C1 cell line) This was evidenced by a low inducible nitric oxide synthase (iNOS) level in macrophages and by an increase in Arg and COX-2 mRNA expression. This is highlighted by the upregulation of pro-inflammatory markers (M1 phenotype) such as human leukocyte antigen-cell surface receptor (HLA-DR) and CD86, and by the downregulation of anti-inflammatory markers (M2 phenotype) such as decreased mRNA expression of CD163, MRC1 (C-type mannose receptor 1, CD206) and versican (ECM proteoglycan) and reduced secretion of IL-10 In these macrophages, phagocytosis, associated with the M1-like phenotype, was increased after MDI while irradiation did not influence the ability of cocultured macrophages to promote the invasion of cancer cells and angiogenesis, features of M2-like macrophages [104].
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