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.

Keywords: cancer; dendritic cell; immature myeloid cell; macrophage; myeloid-derived suppressor cell; tumor microenvironment.

Figure 1

Progression from HSC to tumor-promoting TIM. The distinct steps in the progression from HSC to TIM occur at different locations and start with amplification and differentiation of the HSC and its progenitors, including the common myeloid progenitor (CMP), granulocyte-monocyte progenitor (GMP), myeloblast (MB), and monocyte-dendritic cell progenitor (MDP) in the bone marrow. New myeloid cells are released into the blood stream ready to migrate to the tumor bed. This process is regulated by molecular signals produced by cancer cells and is further amplified by molecular signals produced by among others TIMs. These factors include granulocyte (G) and granulocyte macrophage (GM) colony stimulating factor (CSF), Fms-like tyrosine kinase 3-ligand (Flt3-L), chemokine (C-C motif) ligand 2 (CCL2), VEGF and S100A8/9. The phenotype of TIMs of human and mouse origin, and their functional hallmarks are shown. For TADCs, TANs, and TAMs the figure is simplified as different subsets with either anti- (stimulatory) or protumor (regulatory) functions are discriminated for these cell types. The figure focuses on the subsets with protumor activity.

Figure 2

Myeloid cells and their role in elimination of cancer cells. Myeloid cells in addition to other immune cell types fulfill unique as well as redundant functions to achieve tumor cell elimination. Nascent cancer cells are detected by NK cells through the expression of specific ligands, e.g., ligands for the receptor NKG2D. This results in NK cell-mediated killing of the cancer cells, which can be further enhanced through the activation of macrophages and DCs through binding of their receptor dectin-1 to N-glycan structures expressed on certain tumor cells. Cancer cell fragments as well as cancer cells expressing surface calreticulin can be ingested by macrophages (provided that SIRPα is not activated) and DCs. As such these antigen-presenting cells acquire TAAs and can activate CD4⁺ and CD8⁺ T cells. IFN-γ produced by these T cells as well as NK cells is one of the mechanisms exploited to kill cancer cells. This cancer cell killing can be further amplified by activation of the tumoricidal program (NO and TNF-α release) of macrophages via IFN-γ.

Figure 3

Main roles played by the myeloid cells during the escape of cancer cells from immune mediated destruction. Soluble factors secreted by tumor and immune cells, like CCL2, IL-4, IL-6, IL-8, IL-10, IL-13, GM-CSF, M-CSF, VEGF, and SCF create a TME in which arriving and local myeloid cells are molded into immunosuppressive TIMs. Of these, TAM2, TAN2, and MDSCs are the most abundant, while tolDCs are less frequent in the TME. Cytokines like IL-10 and TGF-β extensively contribute in creating the immunosuppressive TME. These TIMs moreover express a multitude of enzymes (e.g., IDO, ARG-1, iNOS) and surface markers (e.g., CD40, CD80, PD-L1) that support them to dampen antitumor immunity. Moreover, TIMs are not only instructed to suppress antitumor responses under influence of growth factors and cytokines in the TME, they are further instructed to perform activities that are in tune with the needs of the tumor cells. These activities include sustaining chronic inflammation, promoting neo-angiogenesis, tumor growth, invasion and metastasis. These activities are mediated by secretion of soluble factors (e.g., cytokines, growth factors, and proteases). These are not shown in the figure.

Figure 4

The dual role of myeloid cells in anticancer therapy responses. (A) RT and CT regimens can induce ICD, thereby alarming antigen-presenting cells (APCs) of the danger that is posed by cancer cells. This alarm is given through the release of various DAMPs (e.g., HMGB1, ATP, et cetera) and facilitates cross priming of tumor-specific CD8⁺ T cells in tumor draining lymph nodes. Activated CD8⁺ T cells subsequently infiltrate the tumor in search of TAA-expressing cancer cells, and upon recognition exploit various mechanisms to kill cancer cells. While, TAM1 and TANs can further enhance the efficacy of CT by releasing ROS, thereby enhancing tumor cell death, other TIMs including MDSCs can counteract the effects or RT and CT not in the least by inhibiting CD8⁺ T cells. (B) Within the TME, CD8⁺ T cells are often rendered tolerant via immunosuppressive factors expressed by tolDCs, TAM2, MDSCs, tumor cells (and Tregs). One strategy is expression of PD-L1 that binds to PD-1 on activated T cells. Consequently, immune checkpoint inhibition has been studied to alleviate PD-L1:PD-1 mediated immunosuppression. Monoclonal antibodies are actively used for this purpose, however, were shown to be captured by TAMs using their FcγR and were shown to be counteracted by MDSCs. Nonetheless, the success of immune checkpoint inhibition is correlated to the presence of immunostimulatory TIMs and CD8⁺ T cells within the TME. (C) Small molecule inhibitors targeting protein kinases implicated in tumor cell progression have been shown to exert effects on TIMs. Some of these effects are beneficial for therapy outcome. For instance BRAF inhibitors revert the suppression exerted by melanoma cells on TADCs. However the majority of these effects potentiate TIMs to exert tumor-promoting functions or prevent TIMs from entering the TME to oppose tumor growth. Examples hereof are Imatinib that stimulates TAM1 to TAM2 polarization, BRAF inhibitors that restore the MDSC compartment through induction of CCL2 and MET inhibitors that avoid recruitment of neutrophils with cytotoxic capactity (iNOS mediated NO release).

Figure 5

Tipping the balance toward myeloid cells with an antitumor phenotype. Several approaches have been studied to increase the ratio of anti- over protumor TIMs. These include, depleting or repolarizing tumor-promoting TIMs, and attracting and activating antitumor TIMs.