The immunosuppressive and pro-tumor functions of CCL18 at the tumor microenvironment

Ana Patrícia Cardoso; Marta Laranjeiro Pinto; Flávia Castro; Ângela Margarida Costa; Ângela Marques-Magalhães; Ana Canha-Borges; Tânia Cruz; Sérgia Velho; Maria José Oliveira

doi:10.1016/j.cytogfr.2021.03.005

The immunosuppressive and pro-tumor functions of CCL18 at the tumor microenvironment

Cytokine Growth Factor Rev. 2021 Aug:60:107-119. doi: 10.1016/j.cytogfr.2021.03.005. Epub 2021 Mar 31.

Authors

Ana Patrícia Cardoso¹, Marta Laranjeiro Pinto², Flávia Castro³, Ângela Margarida Costa³, Ângela Marques-Magalhães⁴, Ana Canha-Borges³, Tânia Cruz³, Sérgia Velho⁵, Maria José Oliveira⁶

Affiliations

¹ i3S, Institute for Research and Innovation in Health, University of Porto, Portugal; INEB, Institute of Biomedical Engineering, University of Porto, Portugal. Electronic address: patricia.cardoso@i3s.up.pt.
² CNC, Center for Neuroscience and Cell Biology, University of Coimbra, Coimbra, Portugal.
³ i3S, Institute for Research and Innovation in Health, University of Porto, Portugal; INEB, Institute of Biomedical Engineering, University of Porto, Portugal.
⁴ i3S, Institute for Research and Innovation in Health, University of Porto, Portugal; INEB, Institute of Biomedical Engineering, University of Porto, Portugal; ICBAS, Institute of Biomedical Sciences Abel Salazar, University of Porto, Portugal.
⁵ i3S, Institute for Research and Innovation in Health, University of Porto, Portugal; IPATIMUP, Institute of Pathology and Molecular Immunology, University of Porto, Portugal.
⁶ i3S, Institute for Research and Innovation in Health, University of Porto, Portugal; INEB, Institute of Biomedical Engineering, University of Porto, Portugal; ICBAS, Institute of Biomedical Sciences Abel Salazar, University of Porto, Portugal; Department of Pathology and Oncology, Faculty of Medicine, University of Porto, Portugal.

PMID: 33863622
DOI: 10.1016/j.cytogfr.2021.03.005

Abstract

Chemokines are essential mediators of immune cell trafficking. In a tumor microenvironment context, chemotactic cytokines are known to regulate the migration, positioning and interaction of different cell subsets with both anti- and pro-tumor functions. Additionally, chemokines have critical roles regarding non-immune cells, highlighting their importance in tumor growth and progression. CCL18 is a primate-specific chemokine produced by macrophages and dendritic cells. This chemokine presents both constitutive and inducible expression. It is mainly associated with a tolerogenic response and involved in maintaining homeostasis of the immune system under physiological conditions. Recently, CCL18 has been noticed as an important component of the complex chemokine system involved in the biology of tumors. This chemokine induces T regulatory cell differentiation and recruitment to the tumor milieu, with subsequent induction of a pro-tumor (M2-like) macrophage phenotype. CCL18 is also directly involved in cancer cell-invasion, migration, epithelial-to-mesenchymal transition and angiogenesis stimulation, pinpointing an important role in the promotion of cancer progression. Interestingly, this chemokine is highly expressed in tumor tissues, particularly at the invasive front of more advanced stages (e.g. colorectal cancer), and high levels are detected in the serum of patients, correlating with poor prognosis. Despite the promising role of CCL18 as a biomarker and/or therapeutic target to hamper disease progression, its pleiotropic functions in a context of cancer are still poorly explored. The scarce knowledge concerning the receptors for this chemokine, together with the insufficient insight on the downstream signaling pathways, have impaired the selection of this molecule as an immediate target for translational research. In this Review, we will discuss recent findings concerning the role of CCL18 in cancer, integrate recently disclosed molecular mechanisms and compile data from current clinical studies.

Keywords: Biomarker; Cancer; Chemokine; Immunosuppressive; Therapeutic target; Tumor microenvironment.

Publication types

Research Support, Non-U.S. Gov't
Review

MeSH terms

Chemokines, CC
Epithelial-Mesenchymal Transition
Humans
Neoplasms*
Neovascularization, Pathologic
Signal Transduction
Tumor Microenvironment*

Substances

CCL18 protein, human
Chemokines, CC