Tumor Associated Macrophages: Evolutionary Role in Cancer Therapeutics
DOI:
https://doi.org/10.51985/JBUMDC2021109Keywords:
Cancer, Tumor associated macrophages (TAMs), Tumor microenvironment (TME) and Precision medicineAbstract
Cancer therapeutics have evolved more significantly during the last two decades with increasing focus on precision medicine.
In principle this involves targeted therapies tailored to patients’ cancer-specific molecular attributes. It includes a repertoire
of immunomodulating, and apoptotic agents added to cytotoxic chemotherapy, to increase effectiveness. Tumor Associated
Macrophages (TAMs) are an interesting potential targets for expanding these therapies. These represent a spectrum of
subtypes with anti-inflammatory M1 and pro-tumor M2 being the predominant among all. A large number of studies have
established their central role in modulating the tumor microenvironment (TME) and contributing to tumor initiation, and
progression. Potential therapeutic strategies that modulate TAMs reduce or block monocyte recruitment, induce apoptosis
of TAMs, re-educate TAMs from pro-tumor M2 to anti-tumor M1, among others. This review takes a detailed look at this
evolving landscape.
References
Mattiuzzi C, Lippi G. Current Cancer Epidemiology. J
Epidemiol Glob Health. 2019;9(4):217-222. doi:10.2991
/jegh.k.191008.001
Sung H, Ferlay J, Siegel RL, et al. Global Cancer Statistics
: GLOBOCAN Estimates of Incidence and Mortality
Worldwide for 36 Cancers in 185 Countries. CA Cancer J
Clin. 2021;71(3):209-249. doi:10.3322/caac.21660
Erickson AW, Ghodrati F, Habbous S, et al. HER2-targeted
therapy prolongs survival in patients with HER2-positive
breast cancer and intracranial metastatic disease: a systematic
review and meta-analysis. Neuro-Oncology Advances.
;2(1)doi:10.1093/noajnl/vdaa136
Lin Y, Xu J, Lan H. Tumor-associated macrophages in tumor
metastasis: biological roles and clinical therapeutic applications.
J Hematol Oncol. 2019;12(1):76. doi:10.1186/s13045-019-
-3
Jeong H, Hwang I, Kang SH, Shin HC, Kwon SY. TumorAssociated Macrophages as Potential Prognostic Biomarkers
of Invasive Breast Cancer. J Breast Cancer. Mar 2019;22(1):38-
doi:10.4048/jbc.2019.22.e5
Yang M, Li Z, Ren M, et al. Stromal Infiltration of TumorAssociated Macrophages Conferring Poor Prognosis of Patients
with Basal-Like Breast Carcinoma. J Cancer. 2018;9(13):2308-
doi:10.7150/jca.25155
Hu JM, Liu K, Liu JH, et al. CD163 as a marker of M2
macrophage, contribute to predicte aggressiveness and
prognosis of Kazakh esophageal squamous cell carcinoma.
Oncotarget. 2017;8(13):21526-21538. doi:10.18632/ oncotarget
.15630
Yin S, Huang J, Li Z, et al. The Prognostic and Clinicopathological Significance of Tumor-Associated Macrophages
in Patients with Gastric Cancer: A Meta-Analysis. PLoS One.
;12(1):e0170042. doi:10.1371/journal.pone.0170042
Yang C, Wei C, Wang S, et al. Elevated CD163(+)/CD68(+)
Ratio at Tumor Invasive Front is Closely Associated with
Aggressive Phenotype and Poor Prognosis in Colorectal
Cancer. Int J Biol Sci. 2019;15(5):984-998.
doi:10.7150/ijbs.29836
Krijgsman D, De Vries NL, Andersen MN, et al. CD163 as
a Biomarker in Colorectal Cancer: The Expression on
Circulating Monocytes and Tumor-Associated Macrophages,
and the Soluble Form in the Blood. Int J Mol Sci. 2020;21(16)
doi:10.3390/ijms21165925
Zhao Y, Ge X, Xu X, Yu S, Wang J, Sun L. Prognostic value
and clinicopathological roles of phenotypes of tumourassociated macrophages in colorectal cancer. J Cancer Res
Clin Oncol. 2019;145(12):3005-3019. doi:10.1007/s00432-
-03041-8
Yahaya MAF, Lila MAM, Ismail S, Zainol M, Afizan N.
Tumour-Associated Macrophages (TAMs) in Colon Cancer
and How to Reeducate Them. J Immunol Res. 2019;2019:
doi:10.1155/2019/2368249
Labani-Motlagh A, Ashja-Mahdavi M, Loskog A. The Tumor
Microenvironment: A Milieu Hindering and Obstructing
Antitumor Immune Responses. Front Immunol. 2020;11:940.
doi:10.3389/fimmu.2020.00940
Yuan Y, Jiang Y-C, Sun C-K, Chen Q-M. Role of the tumor
microenvironment in tumor progression and the clinical
applications (Review). Oncol Rep. 2016/05/01 2016;35(5):
-2515. doi:10.3892/or.2016.4660
Wei R, Liu S, Zhang S, Min L, Zhu S. Cellular and Extracellular
Components in Tumor Microenvironment and Their
Application in Early Diagnosis of Cancers. Analytical Cellular
Pathology. 2020/01/08 2020;2020:6283796. doi:10.1155 /2020
/6283796
Arneth B. Tumor Microenvironment. Medicina (Kaunas).
;56(1)doi:10.3390/medicina56010015
Baghban R, Roshangar L, Jahanban-Esfahlan R, et al. Tumor
microenvironment complexity and therapeutic implications
at a glance. Cell Communication and Signaling. 2020/04/07
;18(1): 59. doi:10.1186/s12964-020-0530-4
Chen Y, Song Y, Du W, Gong L, Chang H, Zou Z. Tumorassociated macrophages: an accomplice in solid tumor
progression. J Biomed Sci. 2019;26(1):78. doi:10.1186/s12929-
-0568-z
Yona S, Gordon S. From the Reticuloendothelial to
Mononuclear Phagocyte System – The Unaccounted Years.
Review. Frontiers in Immunology. 2015-July-01
;6(328)doi:10.3389/fimmu.2015.00328
Zhou J, Tang Z, Gao S, Li C, Feng Y, Zhou X. TumorAssociated Macrophages: Recent Insights and Therapies.
Front Oncol. 2020;10:188. doi:10.3389/fonc.2020.00188
Guttman O, C. Lewis E. M2-like macrophages and tumorassociated macrophages: overlapping and distinguishing
properties en route to a safe therapeutic potential. Integrative
Cancer Science and Therapeutics. 2016;3(5) doi:10. 15761
/icst.1000204
Jayasingam SD, Citartan M, Thang TH, Mat Zin AA, Ang
KC, Ch'ng ES. Evaluating the Polarization of TumorAssociated Macrophages Into M1 and M2 Phenotypes in
Human Cancer Tissue: Technicalities and Challenges in
Routine Clinical Practice. Front Oncol. 2019;9:1512.
doi:10.3389/fonc.2019.01512
Pinto ML, Rios E, Duraes C, et al. The Two Faces of TumorAssociated Macrophages and Their Clinical Significance in
Colorectal Cancer. Front Immunol. 2019;10:1875. doi:10
.3389/fimmu.2019.01875
Xu X, Ye J, Huang C, Yan Y, Li J. M2 macrophage-derived
IL6 mediates resistance of breast cancer cells to hedgehog
inhibition. Toxicol Appl Pharmacol. 2019;364:77-82. doi:10.
/j.taap.2018.12.013
Yin Y, Yao S, Hu Y, et al. The Immune-microenvironment
Confers Chemoresistance of Colorectal Cancer through
Macrophage-Derived IL6. Clinical Cancer Research.
;23(23):7375-7387. doi:10.1158/1078-0432.Ccr-17-1283
Tamura R, Tanaka T, Yamamoto Y, Akasaki Y, Sasaki H. Dual
role of macrophage in tumor immunity. Immunotherapy. Aug
;10(10):899-909. doi:10.2217/imt-2018-0006
Cai J, Xia L, Li J, Ni S, Song H, Wu X. Tumor-Associated
Macrophages Derived TGF-â-Induced Epithelial to
Mesenchymal Transition in Colorectal Cancer Cells through
Smad2,3-4/Snail Signaling Pathway. Cancer Res Treat. Jan
;51(1):252-266. doi:10.4143/crt.2017.613
Yang L, Zhang Y. Tumor-associated macrophages: from basic
research to clinical application. Journal of Hematology &
Oncology. 2017/02/28 2017;10(1):58. doi:10.1186/s13045-
-0430-2
Anfray C, Ummarino A, Andón FT, Allavena P. Current
Strategies to Target Tumor-Associated-Macrophages to
Improve Anti-Tumor Immune Responses. Cells. 2019;9(1)
doi:10.3390/cells9010046
Barkal AA, Weiskopf K, Kao KS, et al. Engagement of MHC
class I by the inhibitory receptor LILRB1 suppresses
macrophages and is a target of cancer immunotherapy. Nat
Immunol.2018;19(1):76-84.doi:10.1038/s41590-017-0004-
z
Sanford DE, Belt BA, Panni RZ, et al. Inflammatory Monocyte
Mobilization Decreases Patient Survival in Pancreatic Cancer:
A Role for Targeting the CCL2/CCR2 Axis. Clinical Cancer
Research. 2013;19(13):3404-3415. doi:10.1158/1078-
Ccr-13-0525
Pienta KJ, Machiels J-P, Schrijvers D, et al. Phase 2 study of
carlumab (CNTO 888), a human monoclonal antibody against
CC-chemokine ligand 2 (CCL2), in metastatic castrationresistant prostate cancer. Investigational New Drugs. 2013/
/01 2013;31(3):760-768. doi:10.1007/s10637-012-9869-8
Brana I, Calles A, LoRusso PM, et al. Carlumab, an anti-CC chemokine ligand 2 monoclonal antibody, in combination
with four chemotherapy regimens for the treatment of patients
with solid tumors: an open-label, multicenter phase 1b study.
Target Oncol. 2015;10(1):111-23. doi:10.1007/s11523-014-
-2
Nywening TM, Wang-Gillam A, Sanford DE, et al. Targeting
tumour-associated macrophages with CCR2 inhibition in
combination with FOLFIRINOX in patients with borderline
resectable and locally advanced pancreatic cancer: a singlecentre, open-label, dose-finding, non-randomised, phase 1b
trial. The Lancet Oncology. 2016;17(5):651-662. doi:10.1016
/s1470-2045(16)00078-4
Halama N, Zoernig I, Berthel A, et al. Tumoral Immune Cell
Exploitation in Colorectal Cancer Metastases Can Be Targeted
Effectively by Anti-CCR5 Therapy in Cancer Patients. Cancer
Cell. 2016;29(4):587-601. doi:10.1016/j.ccell.2016.03.005
Diel IJ, Solomayer EF, Costa SD, et al. Reduction in new
metastases in breast cancer with adjuvant clodronate treatment.
N Engl J Med. 1998;339(6):357-63. doi:10.1056/
nejm199808063390601
Powles T, Paterson S, Kanis JA, et al. Randomized, PlaceboControlled Trial of Clodronate in Patients With Primary
Operable Breast Cancer. Journal of Clinical Oncology. 2002;20
(15):3219-3224. doi:10.1200/jco.2002.11.080
Macherey S, Monsef I, Jahn F, et al. Bisphosphonates for
advanced prostate cancer. Cochrane Database Syst Rev. Dec
2017;12(12):Cd006250. doi:10.1002/ 14651858. CD006
pub2
Junankar S, Shay G, Jurczyluk J, et al. Real-time intravital
imaging establishes tumor-associated macrophages as the
extraskeletal target of bisphosphonate action in cancer. Cancer
Discov. 2015;5(1):35-42. doi:10.1158/2159-8290.Cd-14-0621
Ventriglia J, Paciolla I, Cecere SC, et al. Trabectedin in
Ovarian Cancer: is it now a Standard of Care? Clin Oncol (R
Coll Radiol). Aug 2018;30(8):498-503. doi:10. 1016/j.clon.
01.008
Gordon EM, Sankhala KK, Chawla N, Chawla SP. Trabectedin
for Soft Tissue Sarcoma: Current Status and Future
Perspectives. Adv Ther. 2016;33(7):1055-71. doi:10.1007/
s12325-016-0344-3
Ries CH, Cannarile MA, Hoves S, et al. Targeting tumorassociated macrophages with anti-CSF-1R antibody reveals
a strategy for cancer therapy. Cancer Cell. 2014;25(6):846-
doi:10.1016/j.ccr.2014.05.016
Germano G, Frapolli R, Belgiovine C, et al. Role of macrophage
targeting in the antitumor activity of trabectedin. Cancer Cell.
;23(2):249-62. doi:10.1016/j.ccr.2013.01.008
Mantovani A, Marchesi F, Malesci A, Laghi L, Allavena P.
Tumour-associated macrophages as treatment targets in
oncology. Nat Rev Clin Oncol. 2017;14(7):399-416. doi:10.
/nrclinonc.2016.217
Machiels J-P, Gomez-Roca C, Michot J-M, et al. Phase Ib
study of anti-CSF-1R antibody emactuzumab in combination
with CD40 agonist selicrelumab in advanced solid tumor
patients. Journal for ImmunoTherapy of Cancer. 2020;8(2):
e001153. doi:10.1136/jitc-2020-001153
Gomez-Roca CA, Italiano A, Le Tourneau C, et al. Phase I
study of emactuzumab single agent or in combination with
paclitaxel in patients with advanced/metastatic solid tumors
reveals depletion of immunosuppressive M2-like macrophages.
Ann Oncol. 2019;30(8):1381-1392. doi:10.1093/ annonc/
mdz163
van Dalen FJ, van Stevendaal M, Fennemann FL, Verdoes
M, Ilina O. Molecular Repolarisation of Tumour-Associated
Macrophages. Molecules. 2018;24(1)doi: 10.3390/
molecules24010009
Giuseppina Comito1 CPS, Maria Letizia Taddei1, Michele
Lanciotti3 Sergio Serni3, AM, Paola Chiarugi1,2 , Elisa
Giannoni1. Zoledronic acid impairs stromal reactivity by
inhibiting M2-macrophages polarization and prostate cancerassociated fibroblasts. Oncotarget, 2017, Vol 8, (No 1), pp:
-132. 2016;
Gnant M, Mlineritsch B, Stoeger H, et al. Adjuvant endocrine
therapy plus zoledronic acid in premenopausal women with
early-stage breast cancer: 62-month follow-up from the
ABCSG-12 randomised trial. The Lancet Oncology.
;12(7):631-641. doi:10.1016/s1470-2045(11)70122-x
Yan D, Kowal J, Akkari L, et al. Inhibition of colony
stimulating factor-1 receptor abrogates microenvironmentmediated therapeutic resistance in gliomas. Oncogene. 2017;
(43):6049-6058. doi:10.1038/onc.2017.261
Zhu Y, Knolhoff BL, Meyer MA, et al. CSF1/CSF1R blockade
reprograms tumor-infiltrating macrophages and improves
response to T-cell checkpoint immunotherapy in pancreatic
cancer models. Cancer Res. 2014;74(18):5057-69. doi:10.
/0008-5472.Can-13-3723
Liguori M. BC, Pasqualini F., Bergomas F., Pesce S., Sironi
M., Grizzi F., Mantovani A., Belgiovine C., Allavena P.
Functional TRAIL receptors in monocytes and tumorassociated macrophages: . Functional TRAIL receptors in
monocytes and tumor-associated macrophages: A possible
targeting pathway in the tumor microenvironment. Oncotarget.
; 7: 41662-41676.
Advani R, Flinn I, Popplewell L, et al. CD47 Blockade by
Hu5F9-G4 and Rituximab in Non-Hodgkin's Lymphoma. N
Engl J Med. 2018;379(18):1711-1721. doi:10.1056/ NEJMoa
Gordon SR, Maute RL, Dulken BW, et al. PD-1 expression
by tumour-associated macrophages inhibits phagocytosis and
tumour immunity. Nature. 2017;545(7655):495-499.
doi:10.1038/nature22396
Downloads
Published
How to Cite
Issue
Section
License
Copyright (c) 2022 Fouzia Fazal, Muhammad Arsalan Khan, Sumayya Shawana, Muhammad Mubarak
This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License.
Journal of Bahria University Medical & Dental College is an open access journal and is licensed under CC BY-NC 4.0. which permits unrestricted non commercial use, distribution and reproduction in any medium, provided the original work is properly cited. To view a copy of this license, visit https://creativecommons.org/licenses/by-nc/4.0 
