Skip to main content

Advertisement

SpringerLink
Log in

The role of macrophages in anti-tumor immune responses: pathological significance and potential as therapeutic targets

  • Review Article
  • Published:
Human Cell Aims and scope Submit manuscript

Abstract

Malignant tumors comprise various types of normal cells and tumor cells, and are infiltrated by large numbers of immune cells, including macrophages. The results of numerous studies on the function and significance of intratumoral macrophages (tumor-associated macrophages) suggest that these macrophages generally enhance tumor progression rather than act as anti-tumor immune agents. Although much remains unknown, in this review, we attempt to describe the role of macrophages in the tumor microenvironment, and discuss their potential mechanisms on the recent immunotherapy.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

References

  1. Kitamura T, Qian BZ, Pollard JW. Immune cell promotion of metastasis. Nat Rev Immunol. 2015;15:73–86.

    CAS  PubMed  PubMed Central  Google Scholar 

  2. Sica A, Porta C, Amadori A, Pastò A. Tumor-associated myeloid cells as guiding forces of cancer cell stemness. Cancer Immunol Immunother. 2017;66:1025–36.

    CAS  PubMed  Google Scholar 

  3. Komohara Y, Jinushi M, Takeya M. Clinical significance of macrophage heterogeneity in human malignant tumors. Cancer Sci. 2014;105:1–8.

    CAS  PubMed  Google Scholar 

  4. Linde N, Casanova-Acebes M, Sosa MS, et al. Macrophages orchestrate breast cancer early dissemination and metastasis. Nat Commun. 2018;9:21.

    PubMed  PubMed Central  Google Scholar 

  5. Afik R, Zigmond E, Vugman M, et al. Tumor macrophages are pivotal constructors of tumor collagenous matrix. J Exp Med. 2016;213:2315–31.

    CAS  PubMed  PubMed Central  Google Scholar 

  6. Tsukamoto H, Fujieda K, Miyashita A, et al. Combined blockade of IL6 and PD-1/PD-L1 signaling abrogates mutual regulation of their immunosuppressive effects in the tumor microenvironment. Cancer Res. 2018;78:5011–22.

    CAS  PubMed  Google Scholar 

  7. Chen JJ, Yao PL, Yuan A, et al. Up-regulation of tumor interleukin-8 expression by infiltrating macrophages: its correlation with tumor angiogenesis and patient survival in non-small cell lung cancer. Clin Cancer Res. 2003;9:729–37.

    CAS  PubMed  Google Scholar 

  8. Xue J, Schmidt SV, Sander J, et al. Transcriptome-based network analysis reveals a spectrum model of human macrophage activation. Immunity. 2014;40:274–88.

    CAS  PubMed  PubMed Central  Google Scholar 

  9. Tsukamoto H, Kouwaki T, Oshiumi H. Aging-Associated Extracellular Vesicles Contain Immune Regulatory microRNAs alleviating hyperinflammatory state and immune dysfunction in the elderly. iScience. 2020;23:101520.

    CAS  PubMed  PubMed Central  Google Scholar 

  10. Bouchlaka MN, Sckisel GD, Chen M, et al. Aging predisposes to acute inflammatory induced pathology after tumor immunotherapy. J Exp Med. 2013;210:2223–37.

    CAS  PubMed  PubMed Central  Google Scholar 

  11. Mirsoian A, Bouchlaka MN, Sckisel GD, et al. Adiposity induces lethal cytokine storm after systemic administration of stimulatory immunotherapy regimens in aged mice. J Exp Med. 2014;211:2373–83.

    CAS  PubMed  PubMed Central  Google Scholar 

  12. Thevaranjan N, Puchta A, Schulz C, et al. Age-associated microbial dysbiosis promotes intestinal permeability, systemic inflammation, and macrophage dysfunction. Cell Host Microbe. 2018;23(4):570. https://doi.org/10.1016/j.chom.2018.03.006 (Erratum for: Cell Host Microbe. 2017;21(455–466).e4).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Komohara Y, Ohnishi K, Takeya M. Possible functions of CD169-positive sinus macrophages in lymph nodes in anti-tumor immune responses. Cancer Sci. 2017;108:290–5.

    CAS  PubMed  PubMed Central  Google Scholar 

  14. Asano K, Nabeyama A, Miyake Y, et al. CD169-positive macrophages dominate antitumor immunity by crosspresenting dead cell-associated antigens. Immunity. 2011;34:85–95.

    CAS  PubMed  Google Scholar 

  15. Gordon S, Martinez FO. Alternative activation of macrophages: mechanism and functions. Immunity. 2010;32:593–604.

    CAS  PubMed  Google Scholar 

  16. Mills CD. M1 and M2 macrophages: oracles of health and disease. Crit Rev Immunol. 2012;32:463–88.

    CAS  PubMed  Google Scholar 

  17. Martinez FO, Gordon S. The M1 and M2 paradigm of macrophage activation: time for reassessment. F1000Prime Rep. 2014;6:13.

    PubMed  PubMed Central  Google Scholar 

  18. Mantovani A, Marchesi F, Malesci A, Laghi L, Allavena P. Tumour-associated macrophages as treatment targets in oncology. Nat Rev Clin Oncol. 2017;14:399–416.

    CAS  PubMed  PubMed Central  Google Scholar 

  19. Sica A, Mantovani A. Macrophage plasticity and polarization: in vivo veritas. J Clin Invest. 2012;122:787–95.

    CAS  PubMed  PubMed Central  Google Scholar 

  20. Heideveld E, Hampton-O’Neil LA, Cross SJ, van Alphen FPJ, van den Biggelaar M, Toye AM, van den Akker E. Glucocorticoids induce differentiation of monocytes towards macrophages that share functional and phenotypical aspects with erythroblastic island macrophages. Haematologica. 2018;103:395–405.

    CAS  PubMed  PubMed Central  Google Scholar 

  21. Vogelpoel LT, Hansen IS, Rispens T, et al. Fc gamma receptor-TLR cross-talk elicits pro-inflammatory cytokine production by human M2 macrophages. Nat Commun. 2014;5:5444.

    CAS  PubMed  Google Scholar 

  22. Murray PJ, Allen JE, Biswas SK, et al. Macrophage activation and polarization: nomenclature and experimental guidelines. Immunity. 2014;41:14–20.

    CAS  PubMed  PubMed Central  Google Scholar 

  23. Serbina NV, Pamer EG. Monocyte emigration from bone marrow during bacterial infection requires signals mediated by chemokine receptor CCR2. Nat Immunol. 2006;7:311–7.

    CAS  PubMed  Google Scholar 

  24. Tacke F, Alvarez D, Kaplan TJ, et al. Monocyte subsets differentially employ CCR2, CCR5, and CX3CR1 to accumulate within atherosclerotic plaques. J Clin Invest. 2007;117:185–94.

    CAS  PubMed  PubMed Central  Google Scholar 

  25. Jacquelin S, Licata F, Dorgham K, et al. CX3CR1 reduces Ly6Chigh-monocyte motility within and release from the bone marrow after chemotherapy in mice. Blood. 2013;122:674–83.

    PubMed  Google Scholar 

  26. Baghdadi M, Umeyama Y, Hama N, Kobayashi T, Han N, Wada H, Seino KI. Interleukin-34, a comprehensive review. J Leukoc Biol. 2018;104:931–51.

    CAS  PubMed  Google Scholar 

  27. Noyori O, Komohara Y, Nasser H, et al. Expression of IL-34 correlates with macrophage infiltration and prognosis of diffuse large B-cell lymphoma. Clin Transl Immunol. 2019;8:e1074.

    Google Scholar 

  28. Geissmann F, Jung S, Littman DR. Blood monocytes consist of two principal subsets with distinct migratory properties. Immunity. 2003;19:71–82.

    CAS  PubMed  Google Scholar 

  29. Ziegler-Heitbrock L, Ancuta P, Crowe S, et al. Nomenclature of monocytes and dendritic cells in blood. Blood. 2010;116:e74-80.

    CAS  PubMed  Google Scholar 

  30. Jia D, Jiang H, Weng X, et al. Interleukin-35 promotes macrophage survival and improves wound healing after myocardial infarction in mice. Circ Res. 2019;124:1323–36.

    CAS  PubMed  Google Scholar 

  31. Lavin Y, Mortha A, Rahman A, Merad M. Regulation of macrophage development and function in peripheral tissues. Nat Rev Immunol. 2015;15:731–44.

    CAS  PubMed  PubMed Central  Google Scholar 

  32. Mass E, Ballesteros I, Farlik M, et al. Specification of tissue-resident macrophages during organogenesis. Science. 2016;353:aaf4238.

    PubMed  PubMed Central  Google Scholar 

  33. Guilliams M, De Kleer I, Henri S, et al. Alveolar macrophages develop from fetal monocytes that differentiate into long-lived cells in the first week of life via GM-CSF. J Exp Med. 2013;210:1977–92.

    CAS  PubMed  PubMed Central  Google Scholar 

  34. Molawi K, Wolf Y, Kandalla PK, et al. Progressive replacement of embryo-derived cardiac macrophages with age. J Exp Med. 2014;211:2151–8.

    CAS  PubMed  PubMed Central  Google Scholar 

  35. Chen Z, Feng X, Herting CJ, et al. Cellular and molecular identity of tumor-associated macrophages in glioblastoma. Cancer Res. 2017;77:2266–78.

    CAS  PubMed  PubMed Central  Google Scholar 

  36. Aegerter H, Kulikauskaite J, Crotta S, et al. Influenza-induced monocyte-derived alveolar macrophages confer prolonged antibacterial protection. Nat Immunol. 2020;21:145–57.

    CAS  PubMed  PubMed Central  Google Scholar 

  37. Zhu Y, Herndon JM, Sojka DK, et al. Tissue-resident macrophages in pancreatic ductal adenocarcinoma originate from embryonic hematopoiesis and promote tumor progression. Immunity. 2017;47:597.

    CAS  PubMed  Google Scholar 

  38. Soncin I, Sheng J, Chen Q, et al. The tumour microenvironment creates a niche for the self-renewal of tumour-promoting macrophages in colon adenoma. Nat Commun. 2018;9:582.

    PubMed  PubMed Central  Google Scholar 

  39. Friebel E, Kapolou K, Unger S, et al. Single-Cell Mapping Of Human Brain Cancer Reveals Tumor-Specific Instruction Of Tissue-Invading Leukocytes. Cell. 2020;181:1626-1642e20.

    CAS  PubMed  Google Scholar 

  40. Scott CL, Zheng F, De Baetselier P, et al. Bone marrow-derived monocytes give rise to self-renewing and fully differentiated Kupffer cells. Nat Commun. 2016;7:10321.

    CAS  PubMed  PubMed Central  Google Scholar 

  41. Tan SY, Krasnow MA. Developmental origin of lung macrophage diversity. Development. 2016;143:1318–27.

    CAS  PubMed  PubMed Central  Google Scholar 

  42. Chevrier S, Levine JH, Zanotelli VRT, et al. An immune atlas of clear cell renal cell carcinoma. Cell. 2017;169:736-749e18.

    CAS  PubMed  PubMed Central  Google Scholar 

  43. van de Laar L, Saelens W, De Prijck S, et al. Yolk sac macrophages, fetal liver, and adult monocytes can colonize an empty niche and develop into functional tissue-resident macrophages. Immunity. 2016;44:755–68.

    PubMed  Google Scholar 

  44. Lavin Y, Winter D, Blecher-Gonen R, et al. Tissue-resident macrophage enhancer landscapes are shaped by the local microenvironment. Cell. 2014;159:1312–26.

    CAS  PubMed  PubMed Central  Google Scholar 

  45. Schulz M, Michels B, Niesel K, et al. Cellular and molecular changes of brain metastases-associated myeloid cells during disease progression and therapeutic response. iScience. 2020;23:101178.

    CAS  PubMed  PubMed Central  Google Scholar 

  46. Van Overmeire E, Stijlemans B, Heymann F, et al. M-CSF and GM-CSF receptor signaling differentially regulate monocyte maturation and macrophage polarization in the tumor microenvironment. Cancer Res. 2016;76:35–42.

    PubMed  Google Scholar 

  47. Tsukamoto H, Fujieda K, Senju S, Ikeda T, Oshiumi H, Nishimura Y. Immune-suppressive effects of interleukin-6 on T-cell-mediated anti-tumor immunity. Cancer Sci. 2018;109:523–30.

    CAS  PubMed  Google Scholar 

  48. Haist M, Stege H, Grabbe S, Bros M. the functional crosstalk between myeloid-derived suppressor cells and regulatory t cells within the immunosuppressive tumor microenvironment. Cancers (Basel). 2021;13:E210.

    Google Scholar 

  49. Sharma SK, Chintala NK, Vadrevu SK, Patel J, Karbowniczek M, Markiewski MM. Pulmonary alveolar macrophages contribute to the premetastatic niche by suppressing antitumor T cell responses in the lungs. J Immunol. 2015;194:5529–38.

    CAS  PubMed  Google Scholar 

  50. Czystowska-Kuzmicz M, Sosnowska A, Nowis D, et al. Small extracellular vesicles containing arginase-1 suppress T-cell responses and promote tumor growth in ovarian carcinoma. Nat Commun. 2019;10:3000.

    PubMed  PubMed Central  Google Scholar 

  51. Singhal S, Stadanlick J, Annunziata MJ, et al. Human tumor-associated monocytes/macrophages and their regulation of T cell responses in early-stage lung cancer. Sci Transl Med. 2019;11:1500.

    Google Scholar 

  52. Komohara Y, Takemura K, Lei XF, et al. Delayed growth of EL4 lymphoma in SR-A-deficient mice is due to upregulation of nitric oxide and interferon-gamma production by tumor-associated macrophages. Cancer Sci. 2009;100:2160–6.

    CAS  PubMed  Google Scholar 

  53. Fujiwara Y, Hizukuri Y, Yamashiro K, et al. Guanylate-binding protein 5 is a marker of interferon-γ-induced classically activated macrophages. Clin Transl Immunol. 2016;5:e111.

    Google Scholar 

  54. Komohara Y, Fujiwara Y, Ohnishi K, Shiraishi D, Takeya M. Contribution of macrophage polarization to metabolic diseases. J Atheroscler Thromb. 2016;23:10–7.

    CAS  PubMed  Google Scholar 

  55. Chen DS, Mellman I. Oncology meets immunology: the cancer-immunity cycle. Immunity. 2013;39:1–10.

    PubMed  Google Scholar 

  56. Horlad H, Ma C, Yano H, et al. An IL-27/Stat3 axis induces expression of programmed cell death 1 ligands (PD-L1/2) on infiltrating macrophages in lymphoma. Cancer Sci. 2016;107:1696–704.

    PubMed  PubMed Central  Google Scholar 

  57. Lin H, Wei S, Hurt EM, et al. Host expression of PD-L1 determines efficacy of PD-L1 pathway blockade-mediated tumor regression. J Clin Invest. 2018;128:1708.

    PubMed  PubMed Central  Google Scholar 

  58. Umezu D, Okada N, Sakoda Y, et al. Inhibitory functions of PD-L1 and PD-L2 in the regulation of anti-tumor immunity in murine tumor microenvironment. Cancer Immunol Immunother. 2019;68:201–11.

    CAS  PubMed  Google Scholar 

  59. Arlauckas SP, Garris CS, Kohler RH, et al. In vivo imaging reveals a tumor-associated macrophage-mediated resistance pathway in anti-PD-1 therapy. Sci Transl Med. 2017;9:3604.

    Google Scholar 

  60. Lo Russo G, Moro M, Sommariva M, et al. Antibody-Fc/FcR interaction on macrophages as a mechanism for hyperprogressive disease in non-small cell lung cancer subsequent to PD-1/PD-L1 blockade. Clin Cancer Res. 2019;25:989–99.

    CAS  PubMed  Google Scholar 

  61. Gordon SR, Maute RL, Dulken BW, et al. PD-1 expression by tumour-associated macrophages inhibits phagocytosis and tumour immunity. Nature. 2017;545:495–9.

    CAS  PubMed  PubMed Central  Google Scholar 

  62. Krempski J, Karyampudi L, Behrens MD, et al. Tumor-infiltrating programmed death receptor-1+ dendritic cells mediate immune suppression in ovarian cancer. J Immunol. 2011;186:6905–13.

    CAS  PubMed  Google Scholar 

Download references

Funding

This work was supported by JSPS KAKENHI No. 18K07325 to H.T., H.T. was also supported by The Shin-Nihon Foundation of Advanced Medical Research, and The Princess Takamatsu Cancer Research Fund.

Author information

Authors and Affiliations

  1. Department of Immunology, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan

    Hirotake Tsukamoto & Hiroyuki Oshiumi

  2. Division of Clinical Immunology and Cancer Immunotherapy, Center for Cancer Immunotherapy and Immunobiology, Graduate School of Medicine, Kyoto University, Kyoto, Japan

    Hirotake Tsukamoto

  3. Department of Pathology, Graduate School of Medical Sciences, Kumamoto University, Honjo 1-1-1, Chuo-Ku, Kumamoto, 860-8556, Japan

    Yoshihiro Komohara

Authors
  1. Hirotake Tsukamoto
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Yoshihiro Komohara
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Hiroyuki Oshiumi
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Yoshihiro Komohara.

Ethics declarations

Conflicts of interest

No potential conflicts of interest were disclosed.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Tsukamoto, H., Komohara, Y. & Oshiumi, H. The role of macrophages in anti-tumor immune responses: pathological significance and potential as therapeutic targets. Human Cell 34, 1031–1039 (2021). https://doi.org/10.1007/s13577-021-00514-2

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s13577-021-00514-2

Keywords

Search

Navigation