Human Tumor-Associated Macrophage and Monocyte Transcriptional Landscapes Reveal Cancer-Specific Reprogramming, Biomarkers, and Therapeutic Targets

Overview

Journal Cancer Cell

Publisher Cell Press

Specialty Oncology

Date 2019 Apr 2

PMID 30930117

Citations 460

Authors

Luca Cassetta

Stamatina Fragkogianni

Andrew H Sims

Agnieszka Swierczak

Lesley M Forrester

Hui Zhang

Daniel Y H Soong

Tiziana Cotechini

Pavana Anur

Elaine Y Lin

Antonella Fidanza

Martha Lopez-Yrigoyen

Michael R Millar

Alexandra Urman

Zhichao Ai

Paul T Spellman

E Shelley Hwang

J Michael Dixon

Lisa Wiechmann

Lisa M Coussens

Harriet O Smith

Jeffrey W Pollard

Affiliations

Soon will be listed here.

Abstract

The roles of tumor-associated macrophages (TAMs) and circulating monocytes in human cancer are poorly understood. Here, we show that monocyte subpopulation distribution and transcriptomes are significantly altered by the presence of endometrial and breast cancer. Furthermore, TAMs from endometrial and breast cancers are transcriptionally distinct from monocytes and their respective tissue-resident macrophages. We identified a breast TAM signature that is highly enriched in aggressive breast cancer subtypes and associated with shorter disease-specific survival. We also identified an auto-regulatory loop between TAMs and cancer cells driven by tumor necrosis factor alpha involving SIGLEC1 and CCL8, which is self-reinforcing through the production of CSF1. Together these data provide direct evidence that monocyte and macrophage transcriptional landscapes are perturbed by cancer, reflecting patient outcomes.

Citing Articles

SIGLEC1 has the potential to be an immune-related prognostic indicator in colon adenocarcinoma: a study based on transcriptomic data and Mendelian randomization analysis.

Gu J, Wang Y, Zhang H, Gu H, Zhu H Discov Oncol. 2025; 16(1):324.

PMID: 40088346 DOI: 10.1007/s12672-025-02093-2.

Tebentafusp, a T cell engager, promotes macrophage reprogramming and in combination with IL-2 overcomes macrophage immunosuppression in cancer.

Guc E, Treveil A, Leach E, Broomfield A, Camera A, Clubley J Nat Commun. 2025; 16(1):2374.

PMID: 40064880 PMC: 11893752. DOI: 10.1038/s41467-025-57470-w.

Comprehensive evaluation of tumor response better evaluates the efficacy of neoadjuvant chemotherapy and predicts the prognosis in gastric cancer - a post hoc analysis of a single-center randomized controlled trial.

Gan X, Jia Y, Shan F, Ying X, Li S, Zhang Y BMC Cancer. 2025; 25(1):401.

PMID: 40045265 PMC: 11884205. DOI: 10.1186/s12885-024-13372-6.

Blood TCTP as a potential biomarker associated with immunosuppressive features and poor clinical outcomes in metastatic gastric cancer.

Kim H, Jung S, Bang Y, Kim J, Kim H, Lee H J Immunother Cancer. 2025; 13(3).

PMID: 40032602 PMC: 11877152. DOI: 10.1136/jitc-2024-010455.

Bone Marrow Origin of Mammary Phagocytic Intraductal Macrophages (Foam Cells).

Barsky S, Mcphail K, Wang J, Hoffman R, Ye Y Int J Mol Sci. 2025; 26(4).

PMID: 40004162 PMC: 11855042. DOI: 10.3390/ijms26041699.

References

Hanna R, Cekic C, Sag D, Tacke R, Thomas G, Nowyhed H . Patrolling monocytes control tumor metastasis to the lung. Science. 2015; 350(6263):985-90. PMC: 4869713. DOI: 10.1126/science.aac9407. View

Jung K, Heishi T, Khan O, Kowalski P, Incio J, Rahbari N . Ly6Clo monocytes drive immunosuppression and confer resistance to anti-VEGFR2 cancer therapy. J Clin Invest. 2017; 127(8):3039-3051. PMC: 5531423. DOI: 10.1172/JCI93182. View

Cassetta L, Pollard J . Targeting macrophages: therapeutic approaches in cancer. Nat Rev Drug Discov. 2018; 17(12):887-904. DOI: 10.1038/nrd.2018.169. View

Bolger A, Lohse M, Usadel B . Trimmomatic: a flexible trimmer for Illumina sequence data. Bioinformatics. 2014; 30(15):2114-20. PMC: 4103590. DOI: 10.1093/bioinformatics/btu170. View

Sing T, Sander O, Beerenwinkel N, Lengauer T . ROCR: visualizing classifier performance in R. Bioinformatics. 2005; 21(20):3940-1. DOI: 10.1093/bioinformatics/bti623. View

Kim D, Pertea G, Trapnell C, Pimentel H, Kelley R, Salzberg S . TopHat2: accurate alignment of transcriptomes in the presence of insertions, deletions and gene fusions. Genome Biol. 2013; 14(4):R36. PMC: 4053844. DOI: 10.1186/gb-2013-14-4-r36. View

Knupfer H, Preiss R . Significance of interleukin-6 (IL-6) in breast cancer (review). Breast Cancer Res Treat. 2006; 102(2):129-35. DOI: 10.1007/s10549-006-9328-3. View

Beck A, Espinosa I, Edris B, Li R, Montgomery K, Zhu S . The macrophage colony-stimulating factor 1 response signature in breast carcinoma. Clin Cancer Res. 2009; 15(3):778-87. PMC: 2987696. DOI: 10.1158/1078-0432.CCR-08-1283. View

Li C, Luo X, Lin Y, Tang X, Ling L, Wang L . A Higher Frequency of CD14+ CD169+ Monocytes/Macrophages in Patients with Colorectal Cancer. PLoS One. 2015; 10(10):e0141817. PMC: 4625021. DOI: 10.1371/journal.pone.0141817. View

10.

Franklin R, Liao W, Sarkar A, Kim M, Bivona M, Liu K . The cellular and molecular origin of tumor-associated macrophages. Science. 2014; 344(6186):921-5. PMC: 4204732. DOI: 10.1126/science.1252510. View

11.

Anders S, Pyl P, Huber W . HTSeq--a Python framework to work with high-throughput sequencing data. Bioinformatics. 2014; 31(2):166-9. PMC: 4287950. DOI: 10.1093/bioinformatics/btu638. View

12.

Cassetta L, Kajaste-Rudnitski A, Coradin T, Saba E, Della Chiara G, Barbagallo M . M1 polarization of human monocyte-derived macrophages restricts pre and postintegration steps of HIV-1 replication. AIDS. 2013; 27(12):1847-56. DOI: 10.1097/QAD.0b013e328361d059. View

13.

Johnson W, Li C, Rabinovic A . Adjusting batch effects in microarray expression data using empirical Bayes methods. Biostatistics. 2006; 8(1):118-27. DOI: 10.1093/biostatistics/kxj037. View

14.

Trapnell C, Williams B, Pertea G, Mortazavi A, Kwan G, van Baren M . Transcript assembly and quantification by RNA-Seq reveals unannotated transcripts and isoform switching during cell differentiation. Nat Biotechnol. 2010; 28(5):511-5. PMC: 3146043. DOI: 10.1038/nbt.1621. View

15.

Fang W, Jokar I, Zou A, Lambert D, Dendukuri P, Cheng N . CCL2/CCR2 chemokine signaling coordinates survival and motility of breast cancer cells through Smad3 protein- and p42/44 mitogen-activated protein kinase (MAPK)-dependent mechanisms. J Biol Chem. 2012; 287(43):36593-608. PMC: 3476325. DOI: 10.1074/jbc.M112.365999. View

16.

Arwert E, Harney A, Entenberg D, Wang Y, Sahai E, Pollard J . A Unidirectional Transition from Migratory to Perivascular Macrophage Is Required for Tumor Cell Intravasation. Cell Rep. 2018; 23(5):1239-1248. PMC: 5946803. DOI: 10.1016/j.celrep.2018.04.007. View

17.

Huang D, Sherman B, Lempicki R . Systematic and integrative analysis of large gene lists using DAVID bioinformatics resources. Nat Protoc. 2009; 4(1):44-57. DOI: 10.1038/nprot.2008.211. View

18.

Kitamura T, Qian B, Soong D, Cassetta L, Noy R, Sugano G . CCL2-induced chemokine cascade promotes breast cancer metastasis by enhancing retention of metastasis-associated macrophages. J Exp Med. 2015; 212(7):1043-59. PMC: 4493415. DOI: 10.1084/jem.20141836. View

19.

Toth Z, Mezey E . Simultaneous visualization of multiple antigens with tyramide signal amplification using antibodies from the same species. J Histochem Cytochem. 2007; 55(6):545-54. DOI: 10.1369/jhc.6A7134.2007. View

20.

Takeya M, Komohara Y . Role of tumor-associated macrophages in human malignancies: friend or foe?. Pathol Int. 2016; 66(9):491-505. DOI: 10.1111/pin.12440. View