Abstract
Therapeutic approaches that engage immune cells to treat cancer are becoming increasingly utilized in the clinics and demonstrated durable clinical benefit in several solid tumor types. Most of the current immunotherapies focus on manipulating T cells, however, the tumor microenvironment (TME) is abundantly infiltrated by a heterogeneous population of tumor-associated myeloid cells, including tumor-associated macrophages (TAMs), tumor-associated dendritic cells (TADCs), tumor-associated neutrophils (TANs), and myeloid-derived suppressor cells (MDSCs). Educated by signals perceived in the TME, these cells often acquire tumor-promoting properties ultimately favoring disease progression. Upon appropriate stimuli, myeloid cells can exhibit cytoxic, phagocytic, and antigen-presenting activities thereby bolstering antitumor immune responses. Thus, depletion, reprogramming or reactivation of myeloid cells to either directly eradicate malignant cells or promote antitumor T-cell responses is an emerging field of interest. In this review, we briefly discuss the tumor-promoting and tumor-suppressive roles of myeloid cells in the TME, and describe potential therapeutic strategies in preclinical and clinical development that aim to target them to further expand the range of current treatment options.
Highlights
For a long time, tumors were thought to consist mainly of malignant cells, this view changed in the past decades and tumors are considered to behave as organ-like structures that contain besides cancer cells a large array of stromal cells
These tumor-infiltrating stromal cells comprise among others, immune cells, fibroblasts, pericytes, and endothelial cells, which closely interact with the cancer cells, forming the tumor microenvironment (TME) [1]
Only a subset of patients showed a decrease of myeloid-derived suppressor cells (MDSCs) in the tumor microenvironment [224]. Since both MO-MDCSs and tumor-associated macrophages (TAMs) derive from monocytic precursors, many inhibitors described to reduce the abundance of TAMs can be used to inhibit MOMDSC recruitment as well (Table 1)
Summary
Tumors were thought to consist mainly of malignant cells, this view changed in the past decades and tumors are considered to behave as organ-like structures that contain besides cancer cells a large array of stromal cells. The tunicate-derived chemotherapeutic molecule trabectedin demonstrates a cytotoxic activity against circulating monocytes and TAMs by activating the apoptotic pathway via TRAIL, which was successfully tested in several murine tumors models This resulted in a decreased number of mononuclear phagocytes and an increased infiltration of antitumoral effector T cells in the TME [33, 34]. CCL2/CCR2 axis, using an anti-CCL2 antibody [41] or bindarit, which inhibits CCL2 synthesis [42] Another important regulator of monocyte recruitment toward the TME is the CSF-1 receptor, whose inhibition leads to macrophage depletion in several murine and human tumors [43,44,45]. Inhibition of either CCR2 or CSF1R has been shown to decrease the chemotherapy-resistance of pancreatic tumors and to increase the T-cell mediated anti-tumor immune response in mice [48]
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