Friend or Foe? Recent Strategies to Target Myeloid Cells in Cancer

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.

Imaging temozolomide-induced changes in the myeloid glioma microenvironment

“…Many studies reported the importance of targeting MDSCs and GAMMs in glioma, given the highly immunosuppressive nature of these cells 60 - 62 . Various therapeutic approaches to target MDSCs in glioma have been developed with the aim to directly eliminate MDSCs or inhibiting the migration and expansion into the TME 63 . Many of these strategies consist in combination therapies using chemotherapeutic agents like TMZ and immunotherapy 63 , 64 .…”

“…Various therapeutic approaches to target MDSCs in glioma have been developed with the aim to directly eliminate MDSCs or inhibiting the migration and expansion into the TME 63 . Many of these strategies consist in combination therapies using chemotherapeutic agents like TMZ and immunotherapy 63 , 64 . However, the effect of TMZ on MDSCs has not been largely investigated, especially in patients, and further studies are needed.…”

Mechanistic Targets and Nutritionally Relevant Intervention Strategies to Break Obesity–Breast Cancer Links

“…Under obesogenic conditions, the crosstalk between dysregulated adipose tissue, inflammatory mediators and tumor cells can have adverse impacts on BC outcomes ( 92 ). Autocrine and paracrine signaling mechanisms drive anti- and pro-inflammatory signals within the tumor microenvironment, linking inflammation to tumor aggressiveness, disease progression and chemoresistance programs ( 92 , 93 ).…”

“…Under obesogenic conditions, the crosstalk between dysregulated adipose tissue, inflammatory mediators and tumor cells can have adverse impacts on BC outcomes ( 92 ). Autocrine and paracrine signaling mechanisms drive anti- and pro-inflammatory signals within the tumor microenvironment, linking inflammation to tumor aggressiveness, disease progression and chemoresistance programs ( 92 , 93 ). This communication, which also includes other stromal components (i.e., fibroblasts and tumor-adjacent normal tissue), creates a milieu promoting genetic instability that enhances every aspect of BC progression from increasing proliferation, reducing apoptosis, and facilitating angiogenesis, migration, and ultimately metastasis ( 94 ).…”

Targeting Myeloid-Derived Suppressor Cells in Cancer Immunotherapy

“…The most direct MDSC-targeting therapy strategy is to eliminate MDSCs. Treatment with low doses of chemotherapy drugs, such as gemcitabine, 5-fluorouracil (5-FU), paclitaxel, and cisplatin, effectively affects the viability of MDSCs [8,28,105]. Gemcitabine is a selective inhibitor of MDSCs that reduces the number of circulating T regs and the level of TGFβ1 and PMN-MDSCs but not M-MDSCs in the peripheral blood of patients with pancreatic cancer and restores the proliferation and antitumor capacity of effector T cells [106].…”