Targeting tumour-reprogrammed myeloid cells: the new battleground in cancer immunotherapy

Abstract

Tumour microenvironment is a complex ecosystem in which myeloid cells are the most abundant immune elements. This cell compartment is composed by different cell types, including neutrophils, macrophages, dendritic cells, and monocytes but also unexpected cell populations with immunosuppressive and pro-tumour roles. Indeed, the release of tumour-derived factors influences physiological haematopoiesis producing unconventional cells with immunosuppressive and tolerogenic functions such as myeloid-derived suppressor cells. These pro-tumour myeloid cell populations not only support immune escape directly but also assist tumour invasion trough non-immunological activities. It is therefore not surprising that these cell subsets considerably impact in tumour progression and cancer therapy resistance, including immunotherapy, and are being investigated as potential targets for developing a new era of cancer therapy. In this review, we discuss emerging strategies able to modulate the functional activity of these tumour-supporting myeloid cells subverting their accumulation, recruitment, survival, and functions. These innovative approaches will help develop innovative, or improve existing, cancer treatments.

Keywords: Cancer; Cancer immunotherapy; Inflammation; Myeloid-derived suppressor cells (MDSC); Tumour microenvironment (TME).

Fig. 1

Strategies for myeloid cell reprogramming towards an anti-tumor phenotype. Myeloid cells are reprogrammed at epigenetic, transcriptional, and functional levels by tumor cells to support cancer outgrowth. Use of specific inhibitors (red) can deplete them, or avoid their recruitment in tumor. Alternatively, blocking immune suppressive switches (red Ͱ) and activating (green arrow) pro-inflammatory sensors can re-educate myeloid cells to support anti-tumor immunity. ARG1—arginase 1, ATP—adenosine triphosphate, c-FLIP—cellular FLICE (FADD-like IL-1β-converting enzyme)-inhibitory protein, cGAS—cGAMP synthase, CLEVER—common lymphatic endothelial and vascular endothelial receptor, CCR2—C–C motif chemokine receptor 2, cEBP-β—CCAAT/enhancer-binding protein beta, CSF1R—colony-stimulating factor 1 receptor, DNMT3A—DNA cytosine-5-methyltransferase 3, EZH2—enhancer of zeste homolog 2, GPCR—G protein-coupled receptors, HIF—hypoxia-inducible factor, HDAC—histone deacetylase, IDO1—indoleamine 2,3-dioxygenase 1, IL—interleukin, JAK—Janus kinase, MARCO—macrophage receptor, mTOR—mammalian target of rapamycin, NF-κB—nuclear factor kappa-light chain enhancer of activated B cells, NOS2—nitric oxide synthase 2, NOX2—NADPH oxidase, PI3K—phosphoinositide 3-kinases, RNS—reactive nitrogen species, ROS—reactive oxygen species, PDL1—programmed death-ligand 1, SIGLEC—the sialic acid-binding immunoglobulin-like lectin, STAT—signal transducers and activator of transcription, STING—stimulator of interferon genes, TGF—transforming growth factor, TLR – toll-like receptor, TNF—tumor necrosis factor, TREM—triggering receptor expressed on myeloid cells, TYK—tyrosine protein kinase, VEGF—Vascular endothelial growth factor

Fig. 2

Cartoon depicting the dynamics of tumor-induced emergency myelopoiesis. Tumor microenvironment (TME)-derived soluble and bioactive factors (cytokines, growth factors, exosomes, nanoparticles, cells) condition the BM to output corrupted altered myeloid cells (emergency myelopoiesis) which promote primary cancer growth and metastatic spread (lung and lymph nodes). Hematopoietic stem cells (HSCs), in the so-called BM niche, interact with mesenchymal (MSCs) and endothelial cells that regulate HSC dormancy and differentiation into altered progenitors through cytokines and cell contact-dependent signals. Several mechanisms (depicted by dashed lines) will be the focus of future investigations. From these studies, new targets will be identified and exploited for alternative, more effective, and personalised therapeutic approaches for cancer disease