Embryonic Origin and Subclonal Evolution of Tumor-Associated Macrophages Imply Preventive Care for Cancer

Abstract

Macrophages are widely distributed in tissues and function in homeostasis. During cancer development, tumor-associated macrophages (TAMs) dominatingly support disease progression and resistance to therapy by promoting tumor proliferation, angiogenesis, metastasis, and immunosuppression, thereby making TAMs a target for tumor immunotherapy. Here, we started with evidence that TAMs are highly plastic and heterogeneous in phenotype and function in response to microenvironmental cues. We pointed out that efforts to tear off the heterogeneous "camouflage" in TAMs conduce to target de facto protumoral TAMs efficiently. In particular, several fate-mapping models suggest that most tissue-resident macrophages (TRMs) are generated from embryonic progenitors, and new paradigms uncover the ontogeny of TAMs. First, TAMs from embryonic modeling of TRMs and circulating monocytes have distinct transcriptional profiling and function, suggesting that the ontogeny of TAMs is responsible for the functional heterogeneity of TAMs, in addition to microenvironmental cues. Second, metabolic remodeling helps determine the mechanism of phenotypic and functional characteristics in TAMs, including metabolic bias from macrophages' ontogeny in macrophages' functional plasticity under physiological and pathological conditions. Both models aim at dissecting the ontogeny-related metabolic regulation in the phenotypic and functional heterogeneity in TAMs. We argue that gleaning from the single-cell transcriptomics on subclonal TAMs' origins may help understand the classification of TAMs' population in subclonal evolution and their distinct roles in tumor development. We envision that TAM-subclone-specific metabolic reprogramming may round-up with future cancer therapies.

Keywords: cancer target therapy; heterogeneity; metabolism; origins; subclonal evolution; therapy-resistant; tumor-associated macrophages (TAMs).

Figure 1

The origin and functional heterogeneity of tumor-associated macrophages (TAMs). There are two main origins of TAMs: tissue-resident macrophages (TRMs) and hematopoietic stem and progenitor cell (HSPC)-dependent monocytes. Most TRMs originate from the yolk sac and fetal liver. Under steady-state conditions, TRMs self-maintain in situ throughout adult life and are restrictedly contributed by circulating monocytes from HSPCs, depending on organs and increases in age. Monocyte-derived TAMs originate from not only bone marrow HSPCs but also splenic myeloid-biased HSPCs induced by cancer. Tumor-derived factors mediate the expansion and differentiation of myeloid-biased HSPCs and the recruitment and differentiation of monocytes and myeloid-derived suppressor cells (MDSCs). Tissue-resident TAMs and monocyte-derived TAMs (moTAMs) have different functions in tumor progression. EMT: epithelial-mesenchymal transition; HSPCs: hematopoietic stem and progenitor cells; MDSCs: myeloid-derived suppressor cells; TAMs: tumor-associated macrophages; TRMs: tissue-resident macrophages.

Figure 2

Glucose and lipid metabolism in TAMs. TAMs exhibit a pronounced glycolytic signature enhanced lipid uptake and accumulation. Glucose-derived pyruvate is partly converted to acetyl-CoA by the PDH complex to fuel the TCA cycle, supporting OXPHOS. ATP, from both glycolysis and OXPHOS, can be used to activate the JAK–STAT6 pathway in M2-like activation. 2-DG inhibits TAM phenotype and function due to impaired OXPHOS in addition to glycolysis. Activation of the JAK–STAT6 pathway induces gene expression related to FAO and FA uptake. The caspase1-mediated cleavage of PPARγ attenuates MCAD activity, and FAO promotes LD formation. The elevated level of the scavenger receptor CD36 plays a crucial role in lipid uptake and accumulation in TAMs. The LD formation is essential for TAMs as a stable source of fatty acids for fatty acid oxidation (FAO). Acetyl-CoA converted from citrate feeds FA synthesis and acetylates histones to regulate TAM gene expression. Etomoxir, an inhibitor of CPT1, inhibits FAO and inhibits complex I of the electron transport chain and depletes CoA, eventually impairing M2 activation and the protumor growth activity of TAMs. 2-DG: 2-deoxyglucose; αKG: α-ketoglutarate; CoA: coenzyme A; CPT: carnitine palmitoyltransferase; FA: fatty acid; LD: lipid droplet; MCAD: medium-chain acyl-CoA dehydrogenase; MGLL: monoacylglycerol lipase; OAA: oxaloacetate; OXPHOS: oxidative phosphorylation; PDH: pyruvate dehydrogenase; PDK1: pyruvate dehydrogenase kinase 1; TAMs: tumor-associated macrophages; TCA: tricarboxylic acid.

Figure 3

The metabolic regulation of TAMs’ ontogeny. Embryonic TRMs in the peritoneum display decreased glycolysis and increased OXPHOS compared with monocyte-derived peritoneal macrophages due to mTORC2/FOXO1 axis. Higher FOXO1 expression is also observed in other TRMs (in the lung, spleen, skin, and liver) compared with MDMs, indicating this metabolic bias’s tissue universality. Embryonic TRMs and bone marrow MDMs constitute TAM pools in various tumor types. The metabolic imprints in TAMs from different origins may play an essential role in TAM heterogeneity. TRMs: tissue-resident macrophages; MDMs: monocyte-derived macrophages. TAMs: tumor-associated macrophages.