The Influence of Tumor Microenvironment on Immune Escape of Melanoma
Abstract
:1. Introduction
2. Immune Cells Present within the Melanoma Microenvironment
2.1. Functions of Immune Cells
Type of Immune Cell | Role in the Anti-Cancer Response |
---|---|
Natural killer cells | By binding to the tumor cells and releasing cytolytic molecules, they cause tumor cell death. They also participate in the recruitment of APCs by the secretion of cytokines [10]. |
Macrophages, neutrophils, dendritic cells | Phagocytosis of dead melanoma cells and presentation of cancer antigens that activate secondary adaptive immune responses [10,11]. |
Th (helper) cells | Binding to the APCs via MHC class II protein complex and secretion of cytokines, eventually leading to tumor cell death [15]. |
Teff/Tc (effector/cytotoxic) cells | Recognition of antigens presented by immune cells via MHC class I molecules and induction of a cytotoxic effect in tumor cells [10,13]. |
Treg (regulatory) cells | Secretion of cytokines and chemokines with immunosuppressive activity [16,17]. |
2.2. T Lymphocytes and T Cell-Related Immunotherapy
2.2.1. CTLA-4 and PD-1/PD-L1
Drug Name | Therapeutic Target and Effect |
---|---|
Ipilimumab | Human monoclonal IgG1 anti-CTLA-4 antibody blocking inhibitory signaling based on CTLA-4 [27]. |
Nivolumab | Human monoclonal IgG4 anti-PD-1 antibody binding to PD-1, thereby preventing interaction between this receptor and its ligands present in the tumor niche [28]. |
Pembrolizumab | Fully humanized monoclonal IgG4 antibody directed against PD-1, which prevents it from interacting with PD-L1 [28]. |
Atezolizumab | Fully humanized monoclonal IgG1 antibody, interfering with the binding of PD-L1 ligand to its receptors, PD-1 and B7.1 [29]. |
2.2.2. BRAF V600E-Mutated Melanoma
Immunosuppression in the BRAF V600E-Positive Melanoma |
---|
Low T cell infiltration into the tumor [37] |
Increase in the number of immunosuppressive cells—Tregs and MDSCs within the TME [35] |
Inhibition of dendritic cell maturation and, thus, production of TNF-α and IL-12 [35] |
Low expression of melanoma differentiation antigens and a decrease in the level of MHC molecules, which results in diminished recognition of melanoma cells by the immune system [38] |
2.2.3. Potential Markers for Multitargeted Immunotherapy
2.2.4. Metabolic Mechanisms Involved in Melanoma Immunosuppression
Immunosuppressive Factor | Action |
---|---|
Decreased production of arginine | |
High level of adenosine | |
High level of indoleamine 2,3-dioxygenase (IDO) | |
High level of kinurenine |
|
Acidification within the tumor niche | |
Exosomes |
|
3. B Lymphocytes
4. Tumor-Associated Macrophages
5. Myeloid-Derived Suppressor Cells
6. Dendritic Cells
7. Neutrophils
8. Natural Killer Cells
Cell Type | Role in Melanoma Immunosuppression |
---|---|
T lymphocytes | |
B lymphocytes |
|
Tumor-associated macrophages (TAMs) | |
Myeloid-derived suppressor cells (MDSCs) | |
Dendritic cells (DCs) |
|
Neutrophils | |
Natural killer cells (NK cells) |
|
9. Other Elements of the TME Regulating Immune Response
9.1. microRNAs
The Type of Immune Cells | The Immunosuppressive Role of miRNAs | The Name of miRNA |
---|---|---|
T cells | Impaired effector T cells recruitment, increased IL-10 secretion, and regulatory T lymphocytes infiltration | miR-30b/-30d [134] |
Increased PD-L1 expression in BRAF-mutated melanoma | miR-17-5p [140,141] | |
Macrophages | Polarization of macrophages toward the M2 type | miR-21, miR-29a, and miR-125b-5p [143,144,145] |
Enhancement of the expression of CD80, which binds to the CTLA-4 receptor present on T cells, inhibiting their proliferation and function | miR-125b-5p [144] | |
MDSCs | Conversion of monocytes to MDSCs | miRs: -146a, -155, -125b, -100, -125a, -146b, -99b, and let-7e [135] |
MDSC induction in IL-1βHIGH melanoma | miR-155 [145] | |
TGF-β1-dependent increased accumulation and activity of MDSCs | miR-494 [146] | |
NK cells | Diminished recognition of melanoma cells by NK cells through decreased expression of NKG2D ligands | miR- 34a and miR-34c [147] |
The Immunogenic Role of miRNAs | The Name of miRNAs | |
T cells | Positive correlation with anti-PD-L1 therapy efficiency | miR-16-5p, miR-17-5p, and miR-20a-5p [136] |
Decreased PD-L1 expression | miR-28 [141,142] | |
Elevated production of IFN-γ corresponding with diminished migration rate of melanoma cells | miR-146a [137] | |
Macrophages | Polarization of macrophages toward the M1 type | miR-155 [148] |
9.2. Exosomes
9.3. Acidification
9.4. Cancer-Associated Fibroblasts
9.5. Adipose Tissue
9.6. Keratinocytes
10. Conclusions
Funding
Conflicts of Interest
References
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Simiczyjew, A.; Dratkiewicz, E.; Mazurkiewicz, J.; Ziętek, M.; Matkowski, R.; Nowak, D. The Influence of Tumor Microenvironment on Immune Escape of Melanoma. Int. J. Mol. Sci. 2020, 21, 8359. https://doi.org/10.3390/ijms21218359
Simiczyjew A, Dratkiewicz E, Mazurkiewicz J, Ziętek M, Matkowski R, Nowak D. The Influence of Tumor Microenvironment on Immune Escape of Melanoma. International Journal of Molecular Sciences. 2020; 21(21):8359. https://doi.org/10.3390/ijms21218359
Chicago/Turabian StyleSimiczyjew, Aleksandra, Ewelina Dratkiewicz, Justyna Mazurkiewicz, Marcin Ziętek, Rafał Matkowski, and Dorota Nowak. 2020. "The Influence of Tumor Microenvironment on Immune Escape of Melanoma" International Journal of Molecular Sciences 21, no. 21: 8359. https://doi.org/10.3390/ijms21218359