Turn Back the TIMe: Targeting Tumor Infiltrating Myeloid Cells to Revert Cancer Progression

Abstract

Tumor cells frequently produce soluble factors that favor myelopoiesis and recruitment of myeloid cells to the tumor microenvironment (TME). Consequently, the TME of many cancer types is characterized by high infiltration of monocytes, macrophages, dendritic cells and granulocytes. Experimental and clinical studies show that most myeloid cells are kept in an immature state in the TME. These studies further show that tumor-derived factors mold these myeloid cells into cells that support cancer initiation and progression, amongst others by enabling immune evasion, tumor cell survival, proliferation, migration and metastasis. The key role of myeloid cells in cancer is further evidenced by the fact that they negatively impact on virtually all types of cancer therapy. Therefore, tumor-associated myeloid cells have been designated as the culprits in cancer. We review myeloid cells in the TME with a focus on the mechanisms they exploit to support cancer cells. In addition, we provide an overview of approaches that are under investigation to deplete myeloid cells or redirect their function, as these hold promise to overcome resistance to current cancer therapies.

Autofluorescence imaging of 3D tumor-macrophage microscale cultures resolves spatial and temporal dynamics of macrophage metabolism

“…This is consistent with reported time courses of metabolic and genetic changes in co-cultures of tumor cells and monocytes or macrophages 93 . Furthermore, the genetic and metabolic heterogeneity observed here is supported by recent studies that similarly show tumor-associated macrophages adopt a mixture of M1-like and M2-like characteristics and functions [94][95][96][97][98] . This reinforces a model of tumorassociated macrophages with diverse phenotypes 99 , which can be further explored using the methods demonstrated here.…”

Dynamics of blood neutrophil‐related indices during nivolumab treatment may be associated with response to salvage chemotherapy for non‐small cell lung cancer: A hypothesis‐generating study

“…However, the complete response rates were not necessarily high, therefore further immunotherapeutic strategies are needed to cure lung cancer. Myeloid immunosuppressor cells are considered a major obstacle to cancer immunotherapy . Many clinical trials with agents targeting myeloid immunosuppressor cells are ongoing .…”

“…Myeloid immunosuppressor cells are considered a major obstacle to cancer immunotherapy. 30 Many clinical trials with agents targeting myeloid immunosuppressor cells are ongoing. 31 For example, the nuclear hormone liver-X receptor agonist that depletes MDSCs enhances the antitumor activity of tumor-antigen specific T cells as monotherapy or in combination with PD-1 blockade in mice and cancer patients.…”

Enhanced tumor immune surveillance through neutrophil reprogramming due to Tollip deficiency

“…Our data provide a fresh perspective for the emerging and potentially important roles of neutrophils during the modulation of the tumor immune environment. Emerging basic and translational studies with experimental models and human cancer patients suggest complex repertoires of tumor-associated myeloid cells that may either promote or inhibit tumor progression (5,(23)(24)(25)(26). Although the expanded pools of neutrophils within tumor tissues are very well-recognized common features closely correlated with aggravated tumor growth (5-7), it is not well understood how tumor-associated neutrophils are programmed at the molecular level to either facilitate or suppress tumorigenesis.…”