Abstract
The tumor microenvironment (TME) is a complex network of epithelial and stromal cells, wherein stromal components provide support to tumor cells during all stages of tumorigenesis. Among these stromal cell populations are myeloid cells, which are comprised mainly of tumor-associated macrophages (TAM), dendritic cells (DC), myeloid-derived suppressor cells (MDSC), and tumor-associated neutrophils (TAN). Myeloid cells play a major role in tumor growth through nurturing cancer stem cells by providing growth factors and metabolites, increasing angiogenesis, as well as promoting immune evasion through the creation of an immune-suppressive microenvironment. Immunosuppression in the TME is achieved by preventing critical anti-tumor immune responses by natural killer and T cells within the primary tumor and in metastatic niches. Therapeutic success in targeting myeloid cells in malignancies may prove to be an effective strategy to overcome chemotherapy and immunotherapy limitations. Current therapeutic approaches to target myeloid cells in various cancers include inhibition of their recruitment, alteration of function, or functional re-education to an antitumor phenotype to overcome immunosuppression. In this review, we describe strategies to target TAMs and MDSCs, consisting of single agent therapies, nanoparticle-targeted approaches and combination therapies including chemotherapy and immunotherapy. We also summarize recent molecular targets that are specific to myeloid cell populations in the TME, while providing a critical review of the limitations of current strategies aimed at targeting a single subtype of the myeloid cell compartment. The goal of this review is to provide the reader with an understanding of the critical role of myeloid cells in the TME and current therapeutic approaches including ongoing or recently completed clinical trials.
Highlights
Immune cell involvement in inflammatory ailments has long been established; their role in cancer remained unappreciated until the past three decades (Chen and Mellman, 2017)
tumor-associated macrophages (TAM) are strongly linked to therapy resistance and are associated with poor prognosis (Kurahara et al, 2013) due to soluble factors secreted by infiltrating TAMs that contribute to drug resistance, metastasis, and immune evasion (Beatty et al, 2011)
Like TAMs, dendritic cells (DC) have several phenotypes or subtypes which include classical DCs which are specialized in antigen presentation and induction of T cell immunity (Merad et al, 2013), plasmacytoid DCs which produce interferonα which is important in antitumor immunity (Swiecki and Colonna, 2015), and monocytic DCs which differentiate from circulating monocytes and present a pro-inflammatory phenotype (Gopalakrishnan et al, 2018)
Summary
Immune cell involvement in inflammatory ailments has long been established; their role in cancer remained unappreciated until the past three decades (Chen and Mellman, 2017). Like TAMs, DCs have several phenotypes or subtypes which include classical DCs (cDCs) which are specialized in antigen presentation and induction of T cell immunity (Merad et al, 2013), plasmacytoid DCs (pDCs) which produce interferonα which is important in antitumor immunity (Swiecki and Colonna, 2015), and monocytic DCs (mDCs) which differentiate from circulating monocytes and present a pro-inflammatory phenotype (Gopalakrishnan et al, 2018). Another family of myeloid cells are myeloid-derived suppressor cells (MDSCs), which are potent immunosuppressive cells that arise in pathological conditions such as cancer. Our overall goal is to convey to our readers the importance of targeting myeloid cells in cancer, while critically emphasizing the limitations of current monotherapies targeting myeloid cells in malignancies
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