Targeting Immune Regulatory Networks to Counteract Immune Suppression in Cancer
Abstract
:1. Introduction
2. Counteracting MDSCs, a Major Local and Systemic Obstacle to Immune-Mediated Tumor Control
3. Overcoming the Restraining Activity of Tregs on Adaptive Immunity
4. EVs as Conveyors of Immune Suppression, Therapeutic Vehicle and Therapeutic Target in Cancer
5. Tumor Acidity as a Novel Target for Immunomodulation
6. Conclusions
Acknowledgments
Author Contributions
Conflicts of Interest
Abbreviations
CA | carbonic anhydrases |
CTLs | cytotoxic T lymphocytes |
EVs | extracellular vesicles |
ICI | immune checkpoint inhibitors |
MDSCs | myeloid-derived suppressor cells |
Tregs | regulatory T cells |
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Therapeutic Agent | Specification | Histology (Mice and Humans) | Direct or Indirect Effects on MDSCs | References |
---|---|---|---|---|
PF-04136309 | CCR2 inhibitor | Pancreatic cancer | Blocking of MDSC recruitment | [22,23] |
Sunitinib | Tyrosine kinase inhibitor | Metastatic renal cancer, soft tissue sarcoma | Decrease of circulating MDSCs Downregulation of M-MDSCs | [25,27] |
Stattic | Small molecule inhibitor of pSTAT3 | Head and neck squamous cell carcinoma | Targets arginase dependent suppressive function of M-MDSCs | [28] |
Cucurbitacin B (CuB) | JAK2/STAT3 pathway inhibitor | Advanced lung carcinoma | Promotes MDSC differentiation | [29] |
Celecoxib | Cyclooxygenase-2 inhibitor | Melanoma cells | Suppression of melanoma derived M-MDSC activation | [32] |
Sildenafil, tadalafil | Phosphodiesterase-5 (PDE5) inhibitor | Murine colon, breast cancer, fibrosarcoma | Reduction of MDSC functions | [33] |
Tadalafil | Phosphodiesterase-5 (PDE5) inhibitor | Head and neck squamous cell carcinoma | Reduction of circulating MDSCs | [34] |
CDDO-Me; bardoxolone methyl | Triterpenoid | Pancreatic cancer; murine colon, lung, thymus cancer | Abrogation of the suppressive effect of MDSCs | [35] |
Bortezomib | Proteasome inhibitor | Multiple myeloma | Reduction of circulating MDSCs | [36] |
Omaveloxolone (RTA-408) | Triterpenoid | Melanoma | Abrogation of the suppressive effect of MDSCs | NCT02259231 |
Vemurafenib | B-rapidly accelerated fibrosarcoma (BRAF) inhibitor | Melanoma | Inhibition of M-MDSC generation | [37] |
Gemcitabine, 5-fluoruracil, doxorubicin | Chemotherapeutic agent | Murine thymoma, breast cancer | Reduction of MDSC frequency, trafficking and recruitment | [38,39,40] |
25-hydroxyvitamin D(3) | Vitamin | Head and neck cancer, Murine lung carcinoma | Differentiation of MDSCs, reduction of immune suppressive CD34(+) cells | [41,42] |
All-trans retinoic acid (ATRA) | Vitamin | Renal cell cancer | Decrease of MDSCs by induction of differentiation | [43] |
Therapeutic Agent | Specification | Histology (Mice and Humans) | Direct or Indirect Effects on Tregs | Reference |
---|---|---|---|---|
Daclizumab | Monoclonal antibody against CD25 | Advanced melanoma | Treg depletion from the peripheral circulation | [47] |
Ontak (Denileukin Diftitox) | IL-2 diphteria toxin fusion protein | Advanced melanoma | No evident Treg elimination | [48] |
Cyclophosphamide (low dose/metronomic administration) | Chemotherapeutic agent | Advanced cancers Advanced-stage breast cancer | Profound and selective reduction of circulating Tregs, associated with a suppression of their inhibitory functions Only transient Treg reduction, but it induces stable tumor-specific T cell responses, which correlate with improved clinical outcome | [50,51] |
Sorafenib | Tyrosine kinase inhibitor | Renal cell carcinoma | Reduction of the percentage of tumor-infiltrating Tregs | [54] |
Sunitinib | Tyrosine kinase inhibitor | Metastatic renal cancer Soft tissue sarcoma | Decrease of the number of peripheral blood and intratumoral Tregs Reduction of the frequency of circulating Tregs | [27,53] |
Imatinib | Tyrosine kinase inhibitor | Murine leukemia and lymphoma | Decrease of Treg frequency and impairment of immunosuppressive function | [55] |
Anti-CTLA-4 mAb | Immune checkpoint inhibitor | Advanced melanoma | T cell becomes resistant to Treg-mediated suppression It can engage ex vivo nonclassical monocytes resulting in ADCC-mediated lysis of Tregs | [59,60] |
Anti-PD-1 mAb | Immune-checkpoint inhibitor | Advanced melanoma | Down-regulation of intracellular FoxP3 expression | [61] |
Anti-PD-L1 and anti-LAG-3 mAbs | Immune checkpoint inhibitors | Murine Melanoma | Simultaneous blockade of PD-L1 and LAG-3 in vivo overcomes the necessity to deplete tumor-specific Tregs | [65] |
Anti-OX40 and anti-GITR mAbs | Co-stimulatory molecules, TNF receptor superfamily | Murine GVHD | Abrogation of Treg suppression of GVHD | [62] |
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Camisaschi, C.; Vallacchi, V.; Vergani, E.; Tazzari, M.; Ferro, S.; Tuccitto, A.; Kuchuk, O.; Shahaj, E.; Sulsenti, R.; Castelli, C.; et al. Targeting Immune Regulatory Networks to Counteract Immune Suppression in Cancer. Vaccines 2016, 4, 38. https://doi.org/10.3390/vaccines4040038
Camisaschi C, Vallacchi V, Vergani E, Tazzari M, Ferro S, Tuccitto A, Kuchuk O, Shahaj E, Sulsenti R, Castelli C, et al. Targeting Immune Regulatory Networks to Counteract Immune Suppression in Cancer. Vaccines. 2016; 4(4):38. https://doi.org/10.3390/vaccines4040038
Chicago/Turabian StyleCamisaschi, Chiara, Viviana Vallacchi, Elisabetta Vergani, Marcella Tazzari, Simona Ferro, Alessandra Tuccitto, Olga Kuchuk, Eriomina Shahaj, Roberta Sulsenti, Chiara Castelli, and et al. 2016. "Targeting Immune Regulatory Networks to Counteract Immune Suppression in Cancer" Vaccines 4, no. 4: 38. https://doi.org/10.3390/vaccines4040038
APA StyleCamisaschi, C., Vallacchi, V., Vergani, E., Tazzari, M., Ferro, S., Tuccitto, A., Kuchuk, O., Shahaj, E., Sulsenti, R., Castelli, C., Rodolfo, M., Rivoltini, L., & Huber, V. (2016). Targeting Immune Regulatory Networks to Counteract Immune Suppression in Cancer. Vaccines, 4(4), 38. https://doi.org/10.3390/vaccines4040038