The Role of Tumor-Associated Myeloid Cells in Modulating Cancer Therapy

Abstract

Myeloid cells include various cellular subtypes that are distinguished into mononuclear and polymorphonuclear cells, derived from either common myeloid progenitor cells (CMPs) or myeloid stem cells. They play pivotal roles in innate immunity since, following invasion by pathogens, myeloid cells are recruited and initiate phagocytosis and secretion of inflammatory cytokines into local tissues. Moreover, mounting evidence suggests that myeloid cells may also regulate cancer development by infiltrating the tumor to directly interact with cancer cells or by affecting the tumor microenvironment. Importantly, mononuclear phagocytes, including macrophages and dendritic cells (DCs), can have either a positive or negative impact on the efficacy of chemotherapy, radiotherapy as well as targeted anti-cancer therapies. Tumor-associated macrophages (TAMs), profusely found in the tumor stroma, can promote resistance to chemotherapeutic drugs, such as Taxol and Paclitaxel, whereas the suppression of TAMs can lead to an improved radiotherapy outcome. On the contrary, the presence of TAMs may be beneficial for targeted therapies as they can facilitate the accumulation of large quantities of nanoparticles carrying therapeutic compounds. Tumor infiltrating DCs, however, are generally thought to enhance cytotoxic therapies, including those using anthracyclines. This review focuses on the role of tumor-infiltrating and stroma myeloid cells in modulating tumor responses to various treatments. We herein report the impact of myeloid cells in a number of therapeutic approaches across a wide range of malignancies, as well as the efforts toward the elimination of myeloid cells or the exploitation of their presence for the enhancement of therapeutic efficacy against cancer.

Keywords: Tumor-associated myeloid cells; dendritic cells; immunotherapy; macrophages; myeloid cells; nano-immunotherapy.

Figure 1

Myeloid cells may block or facilitate chemotherapy. Chemotherapy induces recruitment of innate immune cells including macrophages and dendritic cells into the treated tumor tissue. Drug treatment may lead to TAM polarization from the M2- to an M1-like phenotype, hindering tumor growth and metastasis. The mechanisms of action utilized by myeloid cells in supporting or blocking chemotherapy are described in the text and summarized in Table 1. DCs, Dendritic cells; TAMs, Tumor-associated macrophages.

Figure 2

Positive and negative feedback loops of TAM activity during radiotherapy. Following high and low irradiation protocols, antigens are released from dying tumor cells and taken up by APCs, such as TAMs, that subsequently activate CD8⁺ T-cells. This causes CTL recruitment and activation that attack solid tumors. Local irradiation may also cause the accumulation of macrophages to the tumor site that promote tumor recurrence mainly via the expression of SDF-1alpha. Ag, Antigen; APCs, antigen presenting cells; CTL, cytotoxic T lymphocytes; TAMs, tumor associated macrophages; SDF-1alpha, stromal cell-derived factor-1 alpha.

Figure 3

Inhibitory immune checkpoint molecules represent targets for cancer therapy. PD-1, PD-L1, TIM-3, and B7 molecules are expressed by subsets of myeloid-derived cells. PD-1 on macrophages interacts with PD-L1 on tumor cells and allows cancer progression by promoting escape from immune surveillance. TAMs also express PD-L1 and B7 molecules that can interact with the PD-1 on T-cells inhibiting the function of the latter. TIM-3 on infiltrating DCs binds to HMGB1 derived from dying tumor cells blocking anti-tumor immune responses. Tumor cells also express Galectin-9 which interacts with TIM-3 on DCs negatively regulating their function. Tumor Associated Macrophages; DCs, dendritic cells; HMGB1, high-mobility group protein 1; TLR, toll-like receptor; RAGE, receptor for advanced glycation end products.