What Do We Have to Know about PD-L1 Expression in Prostate Cancer? A Systematic Literature Review. Part 3: PD-L1, Intracellular Signaling Pathways and Tumor Microenvironment
Abstract
:1. Introduction
2. Results
2.1. Literature Review Results
2.2. Experimental Studies: Intracellular Signaling Pathways Involved in PD-L1 Expression in PC
2.3. Data from The Cancer Genome Atlas (TCGA) Analysis
2.4. Experimental Studies: Overview of Extracellular Factors Involved in PD-L1 Regulation in PC
2.5. IFN-γ
2.6. TGF-β
2.7. IL-17 and TNF-α
2.8. IL-27
2.9. IL-15
2.10. IL-6
2.11. Complement System and Hypoxia
2.12. AREG
3. Discussion
3.1. Tumor Microenvironment and Mechanisms of Tumor Immune-Escape Mediated by the PD-1/PD-L1 Axis: An Overview
- (1)
- Suppression or inadequate activation/boosting of TILs activity:
- -
- reduction of the proliferation of intratumoral cytotoxic T cells
- -
- induction of CD8+ T cell exhaustion: CD8+ T cells may be present but incapable to mediate cytotoxic activity
- -
- increase of CD8+ T cell apoptosis
- -
- inhibition of Tregs apoptosis.
- -
- B cells regulation
- (2)
- Inhibition of function and activation of NK cells (which can kill tumor cells directly without dependence on antibodies or complement factors)
- (3)
- Regulation of the secretion of soluble factors (inhibition of the production of effector cytokines; promotion of the secretion of immunosuppressive cytokines; chemotactic factors recruiting immunosuppressive cells; etc.)
- (4)
- Immunosuppressive effects mediated by TAMs, MDSCs, dendritic cells and other cell-types (stromal cells, adipocytes, etc.): these cells may express PD-L1, recruit other immunosuppressive cells, secrete cytokines, and interact with tumor cells.
3.2. Intratumoral Lymphocytes
3.3. NK Cells
3.4. Tumor-Associated Myeloid Cells
3.5. Dendritic Cells (DC) and Stromal Cells
3.6. Adipocytes
3.7. Comments on the Intracellular Signaling Pathways Involved in PD-L1 Expression
4. Materials and Methods
- Population: patients, tumor cell lines, or mouse models included in studies concerning the role of PD-L1 in PC;
- Intervention: any type of treatment;
- Comparison: no comparisons are expected;
- Outcomes: patient’s status at last follow-up (no evidence of disease, alive with disease, dead of disease), response to therapy, biochemical recurrence-free survival, metastasis-free survival, cancer-specific survival, disease-free survival, clinical failure-free survival, overall-survival, progression-free survival; for experiments on PC cell lines and mouse models, any reported effect on cancer and immune cell migration, proliferation, viability, growth, resistance/response to therapy, cytotoxic/anti-tumor activity, PD-L1 expression, and mice/cell lines survival.
5. Conclusions
Author Contributions
Funding
Acknowledgments
Conflicts of Interest
References
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Factor | Experiment Type | Cell Lines | Effects on PD-L1 | Studied Effect |
---|---|---|---|---|
Check point | ||||
Soluble PD-1 [149] | Co-culture and Docetaxel treatment | DU145 and Jurkat | Act. | ↑ Docetaxel resistance |
Soluble factors produced by stromal cells | ||||
AREG [121] | Conditioned medium | DU145, PC3, LNCaP | ↑ | ↑ Proliferation, migration and invasion |
IL-6 [97] | Conditioned medium | Dentritic cells | ↑ | // |
Soluble factors produced by adipocytes | ||||
Not identified [136] | Co-culture with conditioned medium | C4-2 and NK; CWR22Rv1 and NK | ↑ | ↓ NK cytotoxicity |
Soluble factors produced by macrophages | ||||
Not identified [134] | Co-culture with conditioned medium | C4-2 and NK; CWR22Rv1 and NK | ↑ | ↓ NK cytotoxicity |
Cytokine/Chemokine and Complement factors | ||||
IL-27 [151] | Treatment | PC3 | ↑ | // |
IFN-γ [10,13,94,103,112,119,128,139,152] | Treatment | PC3 | ↑ | // |
IFN-γ [94] | Treatment | Vcap CWR22Rv1, E006AA | ↑ | // |
IFN-γ [126] | Treatment | TRAMP-C2 | ↑ | // |
IFN-γ [13] | Treatment | LASCPC, NCI-H660 | ↑ | // |
IFN-γ [126] | Treatment | DU145 | = | // |
IFN-γ [13,94,128] | Treatment | LNCaP | = | // |
IFN-γ [94] | Treatment | LAPC-4 | = | // |
IFN-γ [13] | Treatment | BPH1, C4-2, CWRR-1 | = | // |
IFN-γ [10,94,112,119,152] | Treatment | DU145 | ↑ | // |
IFN-γ [112] | Treatment | TRAMP-C2 Ras | ↑ | // |
IFN-γ [106] | Treatment | TRAMP-C1, MyC-CaP | ↑ | // |
Ab anti-IL-6 [134,135,136] | Treatment | C4-2, CWR22Rv1 | ↓ | // |
IL-6 [135] | Treatment | C4-2, CWR22Rv1 | ↑ | // |
IL-17 [145] | Treatment | LNCaP | ↑ | // |
TNF-α [145] | Treatment | LNCaP | ↑ | // |
Chemerin [105] | Treatment of co-culture | DU145 and T | ↓ | ↑ T cytotoxicity |
C5a [18] | Treatment | PC3, C4-2 | ↑ | // |
Hypoxia | ||||
[65] | Co-culture | C4-2 and NK; CWR22Rv1 and NK | ↑ | ↓ NK cytotoxicity |
Cell Lines | Origin | IFN-γ Dose | Treatment Time | Detection Method | Effect on PD-L1 |
---|---|---|---|---|---|
BPH1 [13] | Human | 50 mg/mL | 24 h | WB | = |
CWR22Rv1 [94] | Human | 100 U/mL | 48 h | FC | ↑ |
CWRR-1 [13] | Human | 50 mg/mL | 24 h | WB | = |
C4-2 [13] | Human | 50 mg/mL | 24 h | WB | = |
DU145 [126] | Human | 0.5–10–20 ng/mL | 48 h | FC | = |
DU145 [10] | Human | Not reported | Not indicated | RT-PCR, FC | ↑ |
DU145 [94] | Human | 100 U/mL | 48 h | FC | ↑ |
DU145 [112] | Human | 10 ng/mL | 24 h | WB, FC | ↑ |
DU145 [119] | Human | 100 U/mL | 48 h | FC | ↑ |
DU145 [152] | Human | 10 ng | 24 h | FC | ↑ |
E006AA [94] | Human | 100 U/mL | 48 h | FC | ↑ |
LASCPC [13] | Human | 50 mg/mL | 24 h | WB | ↑ |
LAPC-4 [94] | Human | 100 U/mL | 48 h | FC | = |
LNCaP [13] | Human | 50 mg/mL | 24 h | WB | = |
LNCaP [94] | Human | 100 U/mL | 48 h | FC | = |
LNCaP [128] | Human | 10–100 ng/mL | 24 h | FC | = |
MyC-CaP [106] | Mouse | 0.1–1–10 ng/mL | 72 h | FC | ↑ |
NCI-H660 [13] | Human | 50 mg/mL | 24 h | WB | ↑ |
PC3 [10] | Human | Not reported | Not indicated | RT-PCR, FC | ↑ |
PC3 [13] | Human | 50 mg/mL | 24 h | WB | ↑ |
PC3 [94] | Human | 100 U/mL | 48 h | FC | ↑ |
PC3 [103] | Human | 20 ng/mL | 24 h | WB, FC | ↑ |
PC3 [112] | Human | 10 ng/mL | 24 h | WB, FC | ↑ |
PC3 [119] | Human | 100 U/mL | 48 h | FC | ↑ |
PC3 [128] | Human | 10–100 ng/mL | 24 h | FC | ↑ |
PC3 [139] | Human | 100 ng/mL | 24 h | RT-PCR, WB | ↑ |
PC3 [152] | Human | 10 ng | 24 h | FC | ↑ |
TRAMP-C1 [106] | Mouse | 0.1–1–10 ng/mL | 72 h | FC | ↑ |
TRAMP-C2 [126] | Mouse | 0.5–10–20 ng/mL | 48 h | FC | ↑ |
TRAMP-C2 Ras [112] | Mouse | 10 ng/mL | 24 h | WB, FC | ↑ |
Vcap [94] | Human | 100 U/mL | 48 h | FC | ↑ |
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Palicelli, A.; Croci, S.; Bisagni, A.; Zanetti, E.; De Biase, D.; Melli, B.; Sanguedolce, F.; Ragazzi, M.; Zanelli, M.; Chaux, A.; et al. What Do We Have to Know about PD-L1 Expression in Prostate Cancer? A Systematic Literature Review. Part 3: PD-L1, Intracellular Signaling Pathways and Tumor Microenvironment. Int. J. Mol. Sci. 2021, 22, 12330. https://doi.org/10.3390/ijms222212330
Palicelli A, Croci S, Bisagni A, Zanetti E, De Biase D, Melli B, Sanguedolce F, Ragazzi M, Zanelli M, Chaux A, et al. What Do We Have to Know about PD-L1 Expression in Prostate Cancer? A Systematic Literature Review. Part 3: PD-L1, Intracellular Signaling Pathways and Tumor Microenvironment. International Journal of Molecular Sciences. 2021; 22(22):12330. https://doi.org/10.3390/ijms222212330
Chicago/Turabian StylePalicelli, Andrea, Stefania Croci, Alessandra Bisagni, Eleonora Zanetti, Dario De Biase, Beatrice Melli, Francesca Sanguedolce, Moira Ragazzi, Magda Zanelli, Alcides Chaux, and et al. 2021. "What Do We Have to Know about PD-L1 Expression in Prostate Cancer? A Systematic Literature Review. Part 3: PD-L1, Intracellular Signaling Pathways and Tumor Microenvironment" International Journal of Molecular Sciences 22, no. 22: 12330. https://doi.org/10.3390/ijms222212330