AP-1 Transcription Factors as Regulators of Immune Responses in Cancer
Abstract
:1. Introduction
2. Activator Protein-1 (AP-1) Transcription Factors
2.1. Regulation of Immune Response by AP-1 in Genetically Modified Mice
2.2. AP-1 and T-Cell Activation
2.3. AP-1 and T-Cell Anergy or Exhaustion
3. AP-1 and Immune Checkpoint Regulation
3.1. Co-Stimulatory Molecules and AP-1 Transcription Factors
3.1.1. CD28
3.1.2. CD40/CD40L
3.1.3. ICOS/4-1BB
3.2. Co-Inhibitory Molecules
3.2.1. PD-1
3.2.2. PD-L1
3.2.3. CTLA-4
3.2.4. Tregs
4. Conclusions
Author Contributions
Funding
Conflicts of Interest
References
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National Clinical Trials Identifier | Phase | Targeted Therapy/Immunotherapy | Institution | Scheduling | Indications |
---|---|---|---|---|---|
NCT02224781 | III | D + T, Ipi + Nivo or Ipi + Nivo, D + T | University of Alabama at Birmingham Cancer Center | Sequential | Melanoma |
NCT02910700 | II | Nivo + T, with or w/o D | M.D Anderson Cancer Center | Concurrent | Melanoma |
NCT01940809 | I | Ipi w and w/o D, T and/or Nivo | Brigham and Women’s Hospital | Sequential | Melanoma |
NCT02130466 | I/II | Pembro + T + D | Several locations, USA | Combination | Melanoma |
NCT02858921 | II | D + T + Pembro | Several location, Australia | Sequential | Melanoma |
NCT02625337 | II | Pembro + D + T | Antoni van Leeuwenhoek ziekenhuis Amsterdam, | Concurrent | Melanoma |
NCT03149029 | II | Pembro + D + T | Beth Israel Deaconess Medical Center | Concurrent | Melanoma |
NCT02060188 | II | Nivo + Ipi + C | Several locations, USA | Concurrent | Colon Cancer |
NCT02818023 | I | Pembro + V + C | UPMC Cancer Center Hillman Cancer Center | Concurrent | Melanoma |
NCT03273153 | III | Atezo + C | University of South Alabama; Mitchell Cancer Institute | Concurrent | Melanoma |
NCT03013491 | I/II | CX-072 (anti-PD-L1) + V | Several locations, USA | Concurrent | Solid tumors and Lymphoma |
NCT02968303 | II | V + C, Ipi + Nivo | Several locations, The Netherlands | Sequential | Melanoma |
Gene Name | Direction of the Interaction | AP-1 Member | Mechanism | Activity | Cell Type | References |
---|---|---|---|---|---|---|
CD28 | → (upregulates) | cJun | PI3K, JNK and ERK dependent | T-cell activation | [42,60,61,62,63] | |
ICOS | ← (upregulates) | Fra-2 and other AP-1 | TCR/CD28 stimulation/ ICOS promoter binding | Expansion of several T helper subsets and Tregs | T-cells | [77] |
4-1BB | ← (upregulates) | AP-1 | 4-1BB promoter binding. MEK and JNK dependent. | Co-stimulation of T-cells responses | T-cells | [79,80] |
PD-1 | → (upregulates) | BATF | Inhibits T-cell function | T-cells in chronic viral infections | [85] | |
PD-1 | ← (upregulates) | c-Fos | PD-1 promoter binding | Increased tumor burden when expressed in infiltrating T-cells | T-cells in mouse model of lung carcinoma | [86] |
PD-L1 | ← (upregulates) | cJun, JunB | PD-L1 promoter binding | EBV(+) tumor cells | [91] | |
PD-L1 | ← (upregulates) | cJun | MAPK dependent | BRAFi melanoma cell lines | [92] | |
PD-L1 | ← (upregulates) | cJun | PD-L1 promoter binding. MAPK dependent | Lung carcinoma | [93] | |
CTLA-4 | → (downregulates) | AP-1 | MAPK dependent | Inhibits T-cell activation | CD4+ T-cells or T-cell blasts | [102,103] |
FOXP3 | → (downregulates) | cJun, cFos | JNK dependent | Maintains unresponsiveness of Tregs | Natural occurring Tregs | [110] |
FOXP3 | ← (upregulates) | cJun, cFos | FOXP3 promoter binding. JNK dependent | Controls FOXP3 promoter activity | Sepsis model of Tregs | [111] |
FOXP3 | ← (upregulates) | AP-1 | TGFb-induced FOXP3 promoter binding. MAPK dependent | Controls FOXP3 transcriptional activity | Tregs | [113] |
FOXP3 | ← (downregulates) | BATF3 | FOXP3 promoter binding | Transcriptional suppressor of differentiation of Tregs | Tregs | [114] |
ICOS, CTLA-4 | ← (upregulate) | JunB | IRF4 dependent | Loss of JunB in Tregs results in multi-organ autoimmunity | Tregs | [118] |
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Atsaves, V.; Leventaki, V.; Rassidakis, G.Z.; Claret, F.X. AP-1 Transcription Factors as Regulators of Immune Responses in Cancer. Cancers 2019, 11, 1037. https://doi.org/10.3390/cancers11071037
Atsaves V, Leventaki V, Rassidakis GZ, Claret FX. AP-1 Transcription Factors as Regulators of Immune Responses in Cancer. Cancers. 2019; 11(7):1037. https://doi.org/10.3390/cancers11071037
Chicago/Turabian StyleAtsaves, Vasileios, Vasiliki Leventaki, George Z. Rassidakis, and Francois X. Claret. 2019. "AP-1 Transcription Factors as Regulators of Immune Responses in Cancer" Cancers 11, no. 7: 1037. https://doi.org/10.3390/cancers11071037
APA StyleAtsaves, V., Leventaki, V., Rassidakis, G. Z., & Claret, F. X. (2019). AP-1 Transcription Factors as Regulators of Immune Responses in Cancer. Cancers, 11(7), 1037. https://doi.org/10.3390/cancers11071037