A Vaccine against Cancer: Can There Be a Possible Strategy to Face the Challenge? Possible Targets and Paradoxical Effects
Abstract
:1. Introduction
2. Preliminary Considerations Regarding Carcinogenesis and Metastatic Processes
2.1. The Tumor Microenvironment
2.2. The ECM
2.3. TGF-β
2.4. Epithelial-to-Mesenchymal Transition
2.5. CAFs
3. The Pre-Metastatic Niche
4. Immunity and Inflammation
5. Acquired Resistance to Therapy and TME
6. Prophylactic and Therapeutic Cancer Vaccines
7. Discussion
- (a)
- As far as we know, it is impossible to create a vaccine that can protect healthy subjects, because the cause of cancer is not known, and there is probably no single cause toward which we could direct an immune reaction as a vaccine would be able to do.
- (b)
- Instead, it is possible to create a vaccine that is suitable for cancer patients because it is also true that we cannot prevent cancer, but we can prevent metastasis specifically in those patients who do not yet have it.
- (c)
- It is unquestionable that the first step is to locate the target, identifying the player of the metastasis and blocking it; the question that arises is whether there is a single player or many players.
- (d)
- Moreover, when should we intervene? Assuming that we were able to answer these questions, how could we know which condition the patient is in? In other words, what is the stage of the disease at the molecular level, considering that the paradoxical effects appear linked to specific periods in which one effect can be transformed into an opposite one?
- (e)
- With respect to the previous considerations, we propose some possible candidates for a vaccine against cancer:
- (1)
- An ectonucleotidase such as CD39: blocks the formation of adenosine;
- (2)
- LOX: an enzyme involved in ECM remodeling and promoting cancer cell invasion;
- (3)
- FOXO1: enables EMT in breast cancer;
- (4)
- PRRX1: its increase is associated with a poor prognosis in colorectal cancer;
- (5)
- Hh: it was shown to cause tumor progression in breast and cervical cancer;
- (6)
- TGF-β: only in the late stage.
- −
- Establishing appropriate methods to increase O2 concentration in the TME, a feature that increases antitumoral M1 TAMs;
- −
- Finding substances that inhibit the crosstalk between CAFs and cancer cells;
- −
- Identifying specific strategies to increase IFN and generally stimulate the Th1 response.
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
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Intrinsic Paradoxes and Resistance | ||
---|---|---|
Target | Paradoxes | |
GJIC | Increased Cx expression: - Increased survival in prostate, breast, and colorectal cancers - Decreased survival in bladder cancer, esophageal squamous cell carcinoma, and oral squamous cell carcinoma | [63,65,66,67,68,69] |
EMT-FTs | - Pro-metastatic - Tumor suppressor | [72,73,74,75] |
TGF-β | - Stimulation of EMT and cancer cell proliferation - Cancer suppressor via a lethal EMT and promotion of apoptosis | [84,87] |
Hedgehog pathway | - Induction of tumor progression - Inhibition of EMT and a tumor-suppressive effect | [88,89,90] |
Hippo pathway | - YAP/TAZ can be both pro-metastatic and anti-metastatic through the regulation of F-actin | [91,92,96] |
ROS | - As cancer inducers, they activate both EMT and MET - As oncosuppressors, they promote ferroptosis and prevent metastasis | [31,97,98,99] |
FOXO proteins | - FOXO1 is able to promote EMT and metastasis - FOXO3a represses EMT | [109,110] |
Cancer cell metabolism | - Glycolysis in initial stages - Oxidative phosphorylation during EMT - Use of glutamine instead of glucose in metastases | [112,147] |
- Lipid metabolism favors ferroptosis - Oleic acid protects from ferroptosis | [100,113] | |
Resistance to | ||
Downregulation or lack of tumor antigen expression | ICI, adoptive T-cell therapy, RNA vaccine | [208,213,214,215,216] |
Alterations in antigen processing pathways | ICI | [217,218,219,220,221] |
Loss of HLA expression | ICI, adoptive T-cell therapy Therapeutic vaccine composed of autologous tumor cells and BCG in melanoma | [217,218,219,220,221,222,223,224,225] |
BCG vaccine in bladder cancer | [226] | |
Autologous virus-specific T-cell transfer in Merkel cell carcinoma | [227] | |
Expression of multiple immune checkpoints | Neoantigen vaccine combined with ICI | [228] |
TNF-α and IFN-γ antitumoral effects | ICI | [229,230,231,232] |
WNT–β-catenin signaling, PTEN loss | ICI, melanoma-peptide/interleukin-12 vaccine | [233,234,235] |
“Cold” TME | Therapeutic peptide vaccination | [236] |
Extrinsic paradoxes and resistance | ||
Target | Paradoxes | |
ECM remodeling | - In the lung, LOX activity is favored by high oxygen concentration - In other organs, LOX activity is induced by hypoxia through the activation of HIF | [148,149,150,151] |
CAFs | - Transfer of high-energy metabolites to cancer cells via CAV-1 - Loss of CAV-1 leads to EMT | [123,124,125,126] |
- NF-κB signaling promotes protumor inflammation - Tumor-suppressive function of IKKβ/NF-κB | [122,131] | |
Neutrophils | - Prevention of pre-metastatic niche formation (via oxidative stress) - Entrapment of circulating cancer cells helping to form the niche (via NETs) | [143,144,145] |
- Toxic to cancer cells in the absence of TGF-β signaling, whereas when the TGF-β pathway is functional, neutrophils are skewed toward an immunosuppressive phenotype | [146] | |
Tregs | - Activation of neutrophils and macrophages → cytokines → cancer progression - Facilitation of DCs and CTL → antitumor and anti-metastatic effects | [155,156] |
TAMs | - Within normoxic tumoral tissue, the M1 response is ensured - In hypoxic regions, an M2 response prevails | [164,165] |
TGF-β | - During cancer progression, it acts as a tumor suppressor - In the metastasization process, it induces the EMT and invasion of cancer cells | [59] |
Type 1 IFN | - Absence of signaling → enhanced metastatic load and neutrophil accumulation in metastases - Anti-immune program by inducing the expression of immunosuppressive factors (PD-L1, IDO, and IL-10) on DCs → metastasization | [166,167,168,169] |
Chemokines | - CXCL2, CXCL8, CXCL4, CXCL9, CXCL10, CXCL12, CCL2, and CXCR2 → proangiogenic - CXCR3, CXCL9, CXCL10, and CXCL4 → anti-angiogenic | [171] |
Resistance to | ||
Inhibitory receptors (PD1 and/or CTLA-4) | ICI | [237,238] |
Production of immunosuppressive cytokines | ICI | [237,239,240] |
Macrophages (CSF-1, arginase 1, inducible nitric oxide synthase (iNOS) and ROS) | ICI | [176,241,242,243,244] |
Inhibition of systemic and local T-cell activation via Tregs | ICI | [245] |
Polarization of local CD4+ T cells, neutrophils, and monocytes | ICI, NY-ESO-1 vaccination | [246,247] |
DC function | ICI | [248] |
Numbers of Treg cells and MDSCs | ICI, DC-based vaccine, NY-ESO-1 vaccination | [247,249,250] |
CAF-mediated regulation of DC proliferation and migration, T-cell infiltration, recruitment of MDCs through ECM stiffness | ICI, cancer vaccines | [54,239,251,252,253] |
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Zefferino, R.; Conese, M. A Vaccine against Cancer: Can There Be a Possible Strategy to Face the Challenge? Possible Targets and Paradoxical Effects. Vaccines 2023, 11, 1701. https://doi.org/10.3390/vaccines11111701
Zefferino R, Conese M. A Vaccine against Cancer: Can There Be a Possible Strategy to Face the Challenge? Possible Targets and Paradoxical Effects. Vaccines. 2023; 11(11):1701. https://doi.org/10.3390/vaccines11111701
Chicago/Turabian StyleZefferino, Roberto, and Massimo Conese. 2023. "A Vaccine against Cancer: Can There Be a Possible Strategy to Face the Challenge? Possible Targets and Paradoxical Effects" Vaccines 11, no. 11: 1701. https://doi.org/10.3390/vaccines11111701