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Abstract
Simple SummaryTumor-associated macrophages (TAM) represent a leading component of the tumor microenvironment in hematologic malignancies. TAM could display antitumor activity or, conversely, could contribute to tumor growth and survival, depending on their polarization. TAM are polarized towards form M1, with a pro-inflammatory phenotype and an antineoplastic activity, or M2, with an alternately activated phenotype, associated with a poor outcome in patients presenting with leukemia, lymphoma or multiple myeloma. The molecular mechanisms of TAM in different types of hematologic malignancies are different due to the peculiar microenvironment of each disease. TAM could contribute to tumor progression, reduced apoptosis and angiogenesis; a different TAM polarization could explain a reduced treatment response in patients with a similar disease subtype. The aim of our review is to better define the role of TAM in patients with leukemia, lymphoma or multiple myeloma. Finally, we would like to focus on TAM as a possible target for antineoplastic therapy.The tumor microenvironment includes dendritic cells, T-cytotoxic, T-helper, reactive B-lymphoid cells and macrophages; these reactive cells could interplay with malignant cells and promote tumor growth and survival. Among its cellular components, tumor-associated macrophages (TAM) represent a component of the innate immune system and play an important role, especially in hematologic malignancies. Depending on the stimuli that trigger their activation, TAM are polarized towards form M1, contributing to antitumor responses, or M2, associated with tumor progression. Many studies demonstrated a correlation between TAM, disease progression and the patient’s outcome in lymphoproliferative neoplasms, such as Hodgkin lymphoma (HL) and non-Hodgkin lymphoma (NHL), even if with conflicting results. A critical hurdle to overcome is surely represented by the heterogeneity in the choice of the optimal markers and methods used for TAM analysis (gene-expression profile vs. immunohistochemistry, CD163vs. CD68vs. CD163/CD68 double-positive cells). TAM have been recently linked to the development and progression of multiple myeloma and leukemia, with a critical role in the homing of malignant cells, drug resistance, immune suppression and angiogenesis. As such, this review will summarize the role of TAM in different hematologic malignancies, focusing on the complex interplay between TAM and tumor cells, the prognostic value of TAM and the possible TAM-targeted therapeutic strategies.
Highlights
The innate immune system defends the host from infections and non-self antigens in a non-specific manner; it could be involved in the identification and destruction of neoplastic cells [1,2,3]
The results obtained from pre-clinical studies helped to develop clinical studies in acute lymphoblastic leukemia (ALL) patients; the hypothesized prognostic role of tumor-associated macrophages (TAM) in ALL has not been demonstrated in clinical studies, even if macrophages count in patients’ samples was increased compared to healthy subjects
Higher expression of CD163 was associated with poor prognosis in human acute myeloid leukemia (AML), while no correlation with survival was noted for CD68, further suggesting that M2 TAM could be related to a dismal disease outcome, rather than total macrophages count
Summary
The innate immune system defends the host from infections and non-self antigens in a non-specific manner; it could be involved in the identification and destruction of neoplastic cells [1,2,3]. Since the 1990s, immunohistochemical (IHC) analyses have shown many macrophages in the tumor microenvironment (TME) [7,8] This infiltration could be induced by tumor cells by secreting molecules such as chemokine ligands with a C-C motif (CCL) or C-X3-C motif (CXCL) and granulocyte–macrophage colony-stimulating factor (GM-CSF) [9,10,11,12,13]. (alternatively activated), probably representing the 2 extremities of a continuous spectrum [21,22,23] Due to this different polarization, which occurs in the tissue, M1 TAM could provoke a Th-1 response and play an antineoplastic effect leading to tumor suppression, while M2 TAM, with a low antigen-presenting capacity, could promote tumor growth and survival by inducing angiogenesis and immunosuppression [24]. We have extrapolated: disease, methods of TAM determination, TAM markers, the antibodies and the choice of cut-off for high vs. low infiltration, patient number, treatment schedule and the relationship between TAM and disease outcome, especially progression-free survival (PFS) and overall survival (OS)
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