Implications of metabolism-driven myeloid dysfunctions in cancer therapy

Abstract

Immune homeostasis is maintained by an adequate balance of myeloid and lymphoid responses. In chronic inflammatory states, including cancer, this balance is lost due to dramatic expansion of myeloid progenitors that fail to mature to functional inflammatory neutrophils, macrophages, and dendritic cells (DCs), thus giving rise to a decline in the antitumor effector lymphoid response. Cancer-related inflammation orchestrates the production of hematopoietic growth factors and cytokines that perpetuate recruitment and activation of myeloid precursors, resulting in unresolved and chronic inflammation. This pathologic inflammation creates profound alterations in the intrinsic cellular metabolism of the myeloid progenitor pool, which is amplified by competition for essential nutrients and by hypoxia-induced metabolic rewiring at the tumor site. Therefore, persistent myelopoiesis and metabolic dysfunctions contribute to the development of cancer, as well as to the severity of a broad range of diseases, including metabolic syndrome and autoimmune and infectious diseases. The aims of this review are to (1) define the metabolic networks implicated in aberrant myelopoiesis observed in cancer patients, (2) discuss the mechanisms underlying these clinical manifestations and the impact of metabolic perturbations on clinical outcomes, and (3) explore new biomarkers and therapeutic strategies to restore immunometabolism and differentiation of myeloid cells towards an effector phenotype to increase host antitumor immunity. We propose that the profound metabolic alterations and associated transcriptional changes triggered by chronic and overactivated immune responses in myeloid cells represent critical factors influencing the balance between therapeutic efficacy and immune-related adverse effects (irAEs) for current therapeutic strategies, including immune checkpoint inhibitor (ICI) therapy.

Keywords: Cancer therapy; Metabolism; Myeloid-derived suppressor cells; Myelopoiesis; Tumor-associated macrophages.

Fig. 1

Protumor reprogramming of myeloid cells. Tumor-derived factors (TDFs), including cytokines, myeloid growth factors and metabolites, induce transcriptional activities (i.e., expression of cEBPβ, STAT3, p50, and RORC1/RORγ) guiding the enhanced proliferation and lymphoid to myeloid switch of HSCs. In parallel, activation of CSF-dependent induction of iNAMPT provides enhanced NAD-dependent activation of the sirtuin 1 deacetylase, which inhibits the HIF-1α-dependent and p65 NF-κB-dependent transcription of CXCR4. Deactivation of the anchoring signal CXCR4 mobilizes myeloid cells from the bone marrow, allowing peripheral expansion of myeloid populations (monocytes, neutrophils, MDSCs, and DCs). These cells reach the tumor site through the circulation and infiltrate the tumor tissue in response to tumor-derived chemotactic signals (TDCFs) (i.e., CXCL2, CXCL8, CCL2, S100, VEGF, C5a, and CSF1). In particular, DCs and MDSCs enter the secondary lymphoid organs (lymph nodes and spleen), eliciting inhibitory signals to T cells. Once in the tumor, myeloid cells undergo a further step of reprogramming in response to inhibitory molecules (IL-10, TGFβ, adenosine, NO, and PD-L1) and microenvironmental conditions (low glucose levels, hypoxia, and low pH), terminally differentiating into myeloid suppressor cells (TAMs, TANs, MDSCs, and immature DCs). Overall, the tumor-dependent reprogramming of myeloid populations has to be considered a multistep program, which comprises induction of emergency myelopoiesis (enhanced proliferation and the “lymphoid to myeloid” switch), mobilization to the periphery and final intratumor reprogramming. Common myeloid precursors (CMPs), hematopoietic stem cells (HSCs), tumor-derived factors (TDFs), immature DCs (iDCs)

Fig. 2

Interconnections between metabolism, cancer-related inflammation, myelopoiesis, and cancer therapy. Obesity and adipose tissue macrophages (ATMs) promote myeloid cell expansion by releasing various inflammatory cytokines and adipokines that activate selected transcriptional activities (PARs, RORC1/RORγ, and C/EBPβ) affecting HSC proliferation and differentiation. This myelopoietic boost is amplified by cancer cells that release additional myelopoietic factors, including CSFs, IL-1, IL-17, and PGE2. These factors induce myelopoiesis through the upregulation of specialized transcription factors (i.e., p50 NF-κB, STAT3, and PU-1). The production of adenosine, VEGF, and IL-10 by cancer cells induces the tumor-promoting phenotype (IL-10^high/IL-12^low) of iDCs. The emerging myeloid populations are then recruited to the tumor site, where they acquire suppressor phenotypes (TAMs, TANs, MDSCs, and iDCs) and establish an immunosuppressed tumor microenvironment (TME). The tumor site actively hinders the activation of T lymphocytes through the depletion of amino acids, orchestrated by both infiltrating myeloid suppressor cells and cancer cells that express immunosuppressive enzymes (IDO, iNOS, and Arg1). IDO activity, in particular, results in the production of the immunosuppressive catabolite kynurenine (Kyn), which is capable of inducing the expansion of regulatory T (Treg) cells. Further expression of immune checkpoint ligands (i.e., PD-L1) by myeloid suppressor cells contributes to the inhibition of antitumor immunity. The metabolic consequences of obesity also drive the transition of macrophages from “M2-like” to “M1-like” activation, contributing to inflammation-driven insulin resistance (IR). Of note, both obesity and select chemotherapeutics (i.e., irinotecan, etoposide, and platinum) can induce IR, interfere with the energetic balance and affect T cell activation. However, chemotherapy can also enhance antitumor immunity by promoting the immunogenic cell death (ICD) of cancer cells (i.e., anthracyclines, DNA-damaging agents) and by depleting MDSCs (i.e., docetaxel, gemcitabine, and 5-fluorouracil). In line with this, the inhibition of FAO significantly decreases FA uptake and inhibits the immunosuppressive function of MDSCs. Globally, the intersection of the host’s metabolic status, tumor metabolism, cancer inflammation and the quality of myelopoietic output strongly influences the response to therapy. ICD immunogenic cell death, IR insulin resistance, FAO fatty acid oxidation, FA fatty acid