Macrophage diversity in cancer revisited in the era of single-cell omics

Trends in Immunology, Journal Year: 2022, Volume and Issue: 43(7), P. 546 - 563

Published: June 9, 2022

TAMs have diverse functions in cancer, reflecting the heterogenous nature of these immune cells. Here, we propose a new nomenclature to identify TAM subsets.Recent single cell multi-omics technologies, which allow clustering subsets an unbiased manner, significantly advanced our understanding molecular diversity mice and humans.Novel mechanisms potential therapeutic targets been identified that might regulate tumor-promoting function different subsets.TAM opens promising opportunities for envisaging putative cancer treatments. Tumor-associated macrophages (TAMs) multiple potent and, thus, represent important targets. These highlight TAMs. Recent omics technologies However, unifying annotation their signatures is lacking. review recent major studies transcriptome, epigenome, metabolome, spatial with specific focus on We also consensus model present avenues future research. one most abundant types tumors [1.Cassetta L. Pollard J.W. Targeting macrophages: approaches cancer.Nat. Rev. Drug Discov. 2018; 17: 887-904Crossref PubMed Scopus (650) Google Scholar]. Since initial decade ago [2.Qian B.Z. Macrophage enhances tumor progression metastasis.Cell. 2010; 141: 39-51Abstract Full Text PDF (3151) Scholar], functional now widely appreciated, many seminal field [3.Yang M. et al.Diverse microenvironments.Cancer Res. 78: 5492-5503Crossref (202) Scholar, 4.DeNardo D.G. Ruffell B. Macrophages as regulators tumour immunity immunotherapy.Nat. Immunol. 2019; 19: 369-382Crossref (643) 5.Lopez-Yrigoyen al.Macrophage targeting cancer.Ann. N. Y. Acad. Sci. 2021; 1499: 18-41Crossref (25) This array includes promotion growth, lineage plasticity, invasion, remodeling extracellular matrix, crosstalk endothelial, mesenchymal stromal cells, other cells; effects can result progression, metastasis (see Glossary), therapy resistance [6.Mantovani A. al.Tumour-associated treatment oncology.Nat. Clin. Oncol. 2017; 14: 399-416Crossref (1675) Scholar,7.Guc E. Redefining macrophage neutrophil biology metastatic cascade.Immunity. 54: 885-902Abstract (13) With wide application years seen explosion data illustrating cellular heterogeneity resulting unprecedented amount information TAMs, regardless main studies. Links between are emerging. terminology lacking, making direct comparisons full utilization sets difficult. In this review, summarize human data; include traditional nomenclatures, at levels single-cell transcriptomic, epigenomic, metabolic multi-omics, opportunities, directions. subsets. hope will serve starting point help build complete picture dynamic interactions tumor, well microenvironment (TME). A used describe has now-obsolete M1/M2 model, proposed ~20 ago; it separated into two distinct arms: M1 or 'classically' activated; M2 'alternatively' activated, largely based vitro stimulating type 1 2 cytokines [8.Mills C.D. al.M-1/M-2 Th1/Th2 paradigm.J. 2000; 164: 6166-6173Crossref The newer term 'M1-like' phenotype typically described proinflammatory induced by Toll-like receptor (TLR) ligands cytokines, namely IFN-γ TNF-α. Conversely, 'M2-like' having anti-inflammatory characteristics, being activated interleukin (IL)-4 IL-13, producing TGF-β profibrotic factors. nomenclature, albeit used, remains oversimplified [9.Martinez F.O. Gordon S. paradigm activation: time reassessment.F1000Prime Rep. 2014; 6: 13Crossref (2673) Scholar,10.Nahrendorf Swirski F.K. Abandoning network function.Circ. 2016; 119: 414-417Crossref (195) Indeed, significant morphology, function, surface marker expression observed resident-tissue (RTMs) from organs [11.Bleriot C. al.Determinants resident tissue identity function.Immunity. 2020; 52: 957-970Abstract (94) Scholar]; moreover, co-expression both gene almost all [12.Mulder K. al.Cross-tissue landscape monocytes health disease.Immunity. 1883-1900Abstract Therefore, spectrum polarization relates represents more sensible approach describing [10.Nahrendorf Scholar,13.Mosser D.M. Edwards J.P. Exploring activation.Nat. 2008; 8: 958-969Crossref (5864) normal homeostasis, tightly regulated niche-like local environment, recently [14.Guilliams al.Establishment maintenance niche.Immunity. 434-451Abstract (138) Another layer derives origin. Using lineage-tracing mice, illustrated mouse RTMs derived early erythromyeloid progenitors formed either yolk sac fetal liver [15.Geissmann F. al.Blood consist principal migratory properties.Immunity. 2003; 71-82Abstract (2514) Scholar,16.Gomez Perdiguero al.Tissue-resident originate yolk-sac-derived erythro-myeloid progenitors.Nature. 2015; 518: 547-551Crossref (1236) Additionally, adult may derive circulating monocytic precursors (monocytes) bone marrow [17.Cox al.Origins, biology, diseases macrophages.Annu. 39: 313-344Crossref (1) monocyte contribution varies among organs. For example, steady state, microglia central nervous system (CNS) solely [18.Hoeffel G. al.C-Myb(+) progenitor-derived give rise tissue-resident macrophages.Immunity. 42: 665-678Abstract (611) while dermal embryonic origin [19.Kolter J. al.A subset skin contributes surveillance regeneration nerves.Immunity. 50: 1482-1497Abstract (69) appreciated repeatedly reviewed [20.Pathria P. al.Targeting tumor-associated cancer.Trends 40: 310-327Abstract (382) Scholar,21.Guerriero J.L. Macrophages: road less traveled, changing anticancer therapy.Trends Mol. Med. 24: 472-489Abstract (143) Similar counterparts not only its ontogeny, but cues, including type, organ, subanatomic Identifying basis over past [5.Lopez-Yrigoyen advancements unveiling multidimensional complexity manner. research, oncology eventually fully understand cells hopefully use improve precision diagnosis therapy. Single RNA sequencing (scRNA-seq) technology revolutionized providing in-depth transcriptome level [22.Giladi al.Single-cell characterization haematopoietic trajectories homeostasis perturbed haematopoiesis.Nat. Cell Biol. 20: 836-846Crossref (139) substantial advances available experimental techniques bioinformatics pipelines years, scRNA-seq investigate [23.Lawson D.A. al.Tumour resolution.Nat. 1349-1360Crossref (230) Scholar,24.Ren X. al.Insights gained analysis microenvironment.Annu. 583-609Crossref (15) transcriptomic remain Two large-scale pan-cancer provided valuable regarding diversity. One study analyzed myeloid 380 samples across 15 210 patients through combination newly collected eight published [25.Cheng transcriptional atlas infiltrating cells.Cell. 184: 792-809Abstract (111) Comparison consistent presence CD14+ CD16+ tumor-infiltrating (TIMs), LYVE1+ interstitial non-cancer tissues, seven clusters: INHBA+ C1QC+ ISG15+ LNRP3+ SPP1+ compiled mononuclear phagocytes (MNPs) isolated 41 13 types, six common universe, termed MNP-VERSE. Monocyte clusters were then extracted reintegrated generate MoMac-VERSEi. regulatory inference (SCENIC) [26.Aibar al.SCENIC: clustering.Nat. Methods. 1083-1086Crossref (1003) authors classical monocytes, nonclassical five (HES1 TAM, C1Qhi TREM2 IL4I1 proliferating TAMs) Although nomenclatures studies, others, pattern transcriptomics By reviewing journals, found preserved (Table 1). Based signature genes, enriched pathways, predicated naming interferon-primed (IFN-TAMs), (Reg-TAMs), inflammatory cytokine-enriched (Inflam-TAMs), lipid-associated (LA-TAMs), pro-angiogenic (Angio-TAMs), RTM-like (RTM-TAMs), (Prolif-TAMs) Figure 1, Key figure). Furthermore, three TIMs Box 1).Table 1Mouse various TMEsaBlack font: genes clusters; blue protein markers Underline: CITE-seq; Bold: key reported than paper., bAbbreviations: BRCA, breast cancer; CAF, cancer-associated macrophage; CITE-seq, indexing transcriptomes epitopes sequencing; CRC, colorectal CyTOF, Mass cytometry flight; ECM, matrix; ESCA, esophageal carcinoma; GC, gastric HCC, hepatocellular HNC, head neck i.v., intravenous; IF, immunofluorescent staining; INs-seq, intracellular staining LCM, laser capture microdissection; LYM, lymphoma; MEL, melanoma; Mets, metastasis; mIHC, multiplex immunochemistry MMY, myeloma; N/A, available; NPC, nasopharyngeal NSCLC, nonsmall lung OS, osteosarcoma; OVC, ovarian PDAC, pancreatic ductal adenocarcinoma; PRAC, prostate RCC, renal Reg-TAMs, TAMs; SARC, sarcoma; sc-MS, mass spectrometry; SEPN, spinal ependymomas; SKC, ST, transcriptomics; s.c., subcutaneous; macrophages; THCA, thyroid UCEC, uterine corpus endometrial carcinoma.AnnotationSpeciesSignatureTFCancer typeFunction/enriched pathwayAssayRefsIFN-TAMsHumanCASP1, CASP4, CCL2/3/4/7/8, CD274hi, CD40, CXCL2/3/9/10/11, IDO1, IFI6, IFIT1/2/3, IFITM1/3, IRF1, IRF7, ISG15, LAMP3, PDCD1LG2hi, TNFSF10, C1QA/C, CD38, IL4I1, IFI44LSTAT1 IRF1/7BRCACRCCRC metsGBMHCCHNCLYMMELMMYNPCNSCLCOSPDACSEPNTHCAUCECApoptosis regulatorsEnhance proliferationInflammatory responsesPromote Treg entry tumorT exhaustionImmunosuppressionColocalization exhausted T (ST, IF)Decreased antigen presentation (CyTOF)Suppressed activation (in vitro)IFN-α/γ-IFN response signature; IL2/STAT5; IL6/JAK/STAT3scRNA-seqCITE-seqmIHCSTNanoString GeoMx[12.Mulder Scholar,29.Gubin M.M. al.High-dimensional delineates lymphoid compartment during successful immune-checkpoint therapy.Cell. 175: 1014-1030Abstract (165) Scholar,32.Zavidij O. reveals compromised precursor stages myeloma.Nat. Cancer. 1: 493-506Crossref 33.Zhou intratumoral immunosuppressive osteosarcoma.Nat. Commun. 11: 6322Crossref (74) 34.Zhang Q. al.Interrogation microenvironmental ependymomas dual macrophages.Nat. 12: 6867Crossref (0) Scholar,45.Wu al.Spatiotemporal level.Cancer 134-153Crossref (10) Scholar,52.Pombo Antunes A.R. profiling glioblastoma species disease stage competition specialization.Nat. Neurosci. 595-610Crossref (78) Scholar,\81.Wu S.Z. spatially resolved cancers.Nat. Genet. 53: 1334-1347Crossref (47) Scholar,83.Pelka al.Spatially organized multicellular hubs cancer.Cell. 4734-4752Abstract (29) Scholar]CD14+, CD11b+, CD68+, PD-L1hi, PD-L2hi, CD80hi, CD86hi, MHCIIhi, CD86+, MRC1–, SIGLEC1–, HLA-DRlo, CD314+, CD107a+, CD86, TLR4, CD44 (CITE-seq)MouseCcl2/7/8, Cd274, Cxcl9/10/11, Ifit1/2/3, Ifit3, Ifitm1/3, Il7r, Isg15, Nos2, Rsad2, Tnfsf10, Stat1N/ACT26 s.c. CRCCT26 intrasplenic mets modelT3 SARC (s.c.)Orthotopic GL261 GBMIFN signaturescRNA-seqCITE-seqmIHC[29.Gubin Scholar]Inflam-TAMsHumanCCL2/3/4/5/20, CCL3L1, CCL3L3, CCL4L2, CCL4L4, CXCL1/2/3/5/8, G0S2, IL1B, IL1RN, IL6, INHBA, KLF2/6, NEDD9, PMAIP1, S100A8/A9, SPP1EGR3 IKZF1 NFKB1 NFE2L2 RELCRCCRC metsOSSEPNGCRecruiting regulating cellsCNS inflammation-associated chemokinesPromotes inflammationNeutrophil recruitment lumenT interaction (IHC)TNF signaling; WNTImmune check pointsscRNA-seqmIHCNanoString GeoMx[31.Che L.-H. metastases reprogramming preoperative chemotherapy.Cell Discovery. 7: 80Crossref (4) Scholar,33.Zhou Scholar,34.Zhang Scholar,42.Sathe genomic microenvironment.Clin. Cancer 26: 2640-2653Crossref (66) 43.Zhang al.Dissecting underlying premalignant lesions cancer.Cell 27: 1934-1947Abstract (104) 44.Yin H. map development using sequencing.Front. 12728169Crossref 45.Wu Scholar]MouseCxcl1/2/3/5/8, Ccl20, Ccl3l1, Il1rn, Il1b, G0s2, Inhba, Spp1N/ACT26 CRC CT26 modelChemokine productionImmunosuppressionscRNA-seq[45.Wu Scholar]LA-TAMsHumanACP5, AOPE, APOC1, ATF1, C1QA/B/C, CCL18, CD163, CD36, CD63, CHI3L1, CTSB/D/L, F13A1, FABP5, FOLR2, GPNMB, IRF3, LGALS3, LIPA, LPL, MACRO, MerTK, MMP7/9/12, MRC1, NR1H3, NRF1, NUPR1, PLA2G7, RNASE1, SPARC, SPP1, TFDP2, TREM2, ZEB1FOS/JUN HIF1A MAF/MAFB NR1H3 TCF4 TFECBRCACRCCRC metsGBMGCHCCHNCNPCNSCLCOSPDACPhagocytosisPromotion EMTComplement activationECM degradationAntigen processing pathwaysATP biosynthetic processesCanonical M2-like pathwaysFatty acid metabolismImmunosuppressionInflammationIron ion signalingscRNA-seqSMART-seq2CITE-seqmIHCST[12.Mulder Scholar,27.Zilionis R. cancers conserved populations individuals species.Immunity. 1317-1334Abstract (424) Scholar,28.Yang non-small differences sexes.Front. 12756722Google Scholar,30.Zhang analyses inform myeloid-targeted therapies colon 181: 442-459Abstract (246) Scholar,31.Che Scholar,50.Chen Y.P. subtypes associated prognosis carcinoma.Cell 30: 1024-1042Crossref (71) Scholar,81.Wu Scholar]CD9+, CD80+, MAF, CD163lo/-, CD206+/lo, CD71+, CD72+, CD73, ICOSL, CD40LG, Thy-1 (CITE-seq)MouseAcp5, Apoc1, Apoe, C1qa/B/C, Ccl18, Ccl8, Cd163, Cd206, Cd36, Cd63, Ctsb/d/l, Cxcl9, Fabp5, Folr2, Gpnmb, Lgals3, Macro, Mrc1, Trem2MAFCT26 Orthotopic GBM 7940b orthotopic iKras p53 PDAC metsPhagocytosisAntigen presentationFatty metabolismComplement activationscRNA-seqCITE-seqmIHC[45.Wu Scholar,46.Kemp S.B. al.Pancreatic marked complement-high blood tumor–associated macrophages.Life Alliance. 4e202000935Crossref Scholar]Angio-TAMsHumanADAM8, AREG, BNIP3, CCL2/4/20, CD300E, CD44, CD55, CEBPB, CLEC5A, CTSB, EREG, FCN1, FLT1, FN1, HES1, IL8, MIF, OLR1, PPARG, S100A8/9/12, SERPINB2, SLC2A1, SPIC, THBS1, TIMP1, VCAN, VEGFABACH1 CEBPB FOSL2 HIFA KLF5 MAF RUNX1 SPIC TEAD1 ZEB2BRCACRCCRCCRC metsESCAGBMGCHCCMELNPCNPCNSCLCOVCPDACPDAC metsRCCSEPNTHCAUCECAngiogenesisCAF interactionECM proteolysis; ECM interactionPromotion EMTHIF pathway; NF-kB Notch VEGF signalingJuxtaposed PLVAP+/DLL4+ endothelial (IF)scRNA-seqSMART-seq2CITE-seqNanoString GeoMx[25.Cheng Scholar,41.Sharma al.Onco-fetal drives carcinoma.Cell. 183: 377-394Abstract (103) Scholar,49.Raghavan al.Microenvironment drug 6119-6137Abstract Scholar,67.Zhao revealed promoted progression.J. Transl. 454Crossref Scholar]CD52hi, CD163hi, CD206hi, CXCR4+, CD354+, FOSL2, VEGFAMouseArg1, Adam8, Bnip3, Mif, Slc2a1N/AOrthotopic modelHIF signalingAngiogenesisscRNA-seqCITE-seq[52.Pombo Scholar]Reg-TAMsHumanCCL2, CD274, CD80, CHIT1, CX3CR1, HLA-A/C, HLA-DQA1/B1, HLA-DRA/B1/B5, ICOSLG, IL-10, ITGA4, LGALS9, MAC

Language: Английский

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T cells in health and disease

Signal Transduction and Targeted Therapy, Journal Year: 2023, Volume and Issue: 8(1)

Published: June 19, 2023

T cells are crucial for immune functions to maintain health and prevent disease. cell development occurs in a stepwise process the thymus mainly generates CD4

Language: Английский

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Macrophages in health and disease

Cell, Journal Year: 2022, Volume and Issue: 185(23), P. 4259 - 4279

Published: Nov. 1, 2022

Language: Английский

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Physiology and diseases of tissue-resident macrophages

Nature, Journal Year: 2023, Volume and Issue: 618(7966), P. 698 - 707

Published: June 21, 2023

Language: Английский

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Metabolic orchestration of the wound healing response

Cell Metabolism, Journal Year: 2021, Volume and Issue: 33(9), P. 1726 - 1743

Published: Aug. 11, 2021

Language: Английский

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Synovial tissue macrophages in joint homeostasis, rheumatoid arthritis and disease remission

Nature Reviews Rheumatology, Journal Year: 2022, Volume and Issue: 18(7), P. 384 - 397

Published: June 7, 2022

Language: Английский

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Functional states of myeloid cells in cancer

Cancer Cell, Journal Year: 2023, Volume and Issue: 41(3), P. 490 - 504

Published: March 1, 2023

Language: Английский

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The Good and the Bad: Monocytes’ and Macrophages’ Diverse Functions in Inflammation

Cells, Journal Year: 2022, Volume and Issue: 11(12), P. 1979 - 1979

Published: June 20, 2022

Monocytes and macrophages are central players of the innate immune response play a pivotal role in regulation inflammation. Thereby, they actively participate all phases response, from initiating inflammation triggering adaptive through to clearance cell debris resolution In this review, we described mechanisms monocyte macrophage adaptation rapidly changing microenvironmental conditions discussed different forms polarization depending on environmental cues or pathophysiological condition. Therefore, special focus was placed tight pro- anti-inflammatory diverse functions S100A8/S100A9 proteins scavenger receptor CD163 were highlighted, respectively. We paid attention function under pathological conditions.

Language: Английский

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Tissue-Resident Immune Cells in Humans

Annual Review of Immunology, Journal Year: 2022, Volume and Issue: 40(1), P. 195 - 220

Published: Jan. 19, 2022

Tissue-resident immune cells span both myeloid and lymphoid cell lineages, have been found in multiple human tissues, play integral roles at all stages of the response, from maintaining homeostasis to responding infectious challenges resolution inflammation tissue repair. In humans, studying responses tissues is challenging, although recent advances sampling high-dimensional profiling provided new insights into ontogeny, maintenance, functional role tissue-resident cells. Each contains a specific complement resident Moreover, for each lineage share core properties, along with tissue-specific adaptations. Here we propose five-point checklist defining types humans describe currently known features cells, their mechanisms development, putative within various organs. We also consider these aspects context future studies therapeutics.

Language: Английский

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Role of Macrophages in Wound Healing

Cold Spring Harbor Perspectives in Biology, Journal Year: 2022, Volume and Issue: unknown, P. a041216 - a041216

Published: Aug. 30, 2022

Monocytes/macrophages are key components of the body's innate ability to restore tissue function after injury. In most tissues, both embryo-derived tissue-resident macrophages and recruited blood monocyte-derived contribute injury response. The developmental origin injury-associated has a major impact on outcome healing process. Macrophages abundant at all stages repair coordinate progression through different phases healing. They highly plastic cells that continuously adapt their environment acquire phase-specific activation phenotypes. Advanced omics methodologies have revealed vast heterogeneity macrophage phenotypes metabolic status sites in organs. this review, we highlight role origin, link between wound state reprogramming as well fate during resolution wounding

Language: Английский

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