Myeloid-derived suppressor cells (MDSCs) are immune regulatory myeloid cells, which have emerged as critical regulators of tumor progression and therapy resistance through promoting immune suppression and contributing to tumor vasculature development mechanisms (1-6). Human and mice MDSCs differ in surface, cytoplasmic and nuclear markers (2,7,8). MDSCs characterization and functions have been updated time-to-time (9). After decades of MDSC discovery, we have gained ample knowledge that how MDSC works to promote cancer associated immune suppression. However, in the translational era, scientist started exploiting old knowledge to develop next generation therapeutic modalities. In the same line of thought, Apolloni et al. developed a MDSC cell line using mouse MDSCs (CD11b+/Gr-1+) isolated from the spleens of immunosuppressed mice (10). MDSCs were immortalized using a retrovirus encoding the v-myc and v-raf oncogenes, which expressed monocyte/macrophage markers (10). Establishing MDSC cell line has opened a new door for its tremendous applications in cancer therapy.
Recently, a research team led by Dr. Denies has exploited MDSC cell line as a vehicle for cancer gene therapy (11). Scientists delivered IL12 cytokine-gene, which by itself a very potent antitumor cytokine that stimulates T cells and natural killer cells to attack tumor cells. In addition, IL12 has been demonstrated to reprogram MDSCs to immune stimulating cells (12). MDSC cell line may potentially aid in the specific targeting of IL12 to these hard-to-reach malignant regions. This could overcome previous problems of IL12 based therapies (13). Interestingly, transfecting MDSC cell lines with IL12 plasmid DNA using electroporation resulted into rapid and massive influx of pDNA resulting in cytosolic pDNA levels that most likely surpass the activation threshold of the intracellular DNA sensors leading to cell death (14,15). However, pDNA transfection using Lipofectamine 2000 (LF2000) did not cause a significant loss of viability due to more sustained intracellular release of the pDNA with LF2000. After transfection with LF2000, 56% of the MDSCs were transfected with IL12-pDNA expression and biologically relevant amounts of IL-12 were produced (18 ng mL−1), which lasted for at least 24 hours (16). Surprisingly, IL-12 expression caused an upregulation of co-stimulatory molecule CD80 on transfected MDSC cell lines. This substantially could reduce the immunosuppressive capacity of the MDSCs in tumor microenvironment. At the end, authors investigated that using trans-well migration assays, IL-12-transfected MDSCs were still able to migrate to tumor cells (Figure 1).
Authors identified significant advantages of utilizing MDSC cell line in this study (1). Due to immune nature of the cells, MDSCs has strong ability of migrating or infiltrating into tumor microenvironment (5,17), MDSC based cytokine therapy by gene transfer is beneficial considering the short half-life of most cytokines after systemic use (2), and MDSC cell line based therapy has advantages over mesenchymal stem cell based therapies, which required in vitro expansion to get desired amount and showed lower tumor homing with increased risk of protumor properties (3). Therefore, cytokine production using MDSC cell line based cytokine gene therapy can provide a constant source of cytokine within the tumor by avoiding the need of frequent administration of high amounts of cytokine causing potential cytokine-related toxicities. There have been few examples, where MDSCs showed successful delivery of oncolytic viruses and bacteria, suggesting great potential of anti-tumor agent delivery (18,19).
The present in vitro study will provide a basis to follow-up future in vivo studies. Since the MDSC mediated tumor progression is a common phenomenon in solid cancers, study can be translated using several solid tumor models. In addition, IL12 is considered as good candidate, however, several other critical molecules can be overexpressed in MDSC cell lines through gene transfer to investigate and identify the best candidate before any clinical study (20).
Funding: The work was supported by in part grant IRG-14-193-01 by American Cancer Society to BR Achyut and National Institutes of Health grants R01CA160216 and R01CA172048 to AS Arbab.
Conflicts of Interest: The authors have no conflicts of interest to declare.
- Wesolowski R, Markowitz J, Carson WE 3rd. Myeloid derived suppressor cells—a new therapeutic target in the treatment of cancer. J Immunother Cancer 2013;1:10. [Crossref] [PubMed]
- Achyut BR, Arbab AS. Myeloid Derived Suppressor Cells: Fuel the Fire. Biochem Physiol 2014;3:e123. [PubMed]
- Achyut BR. Impact of Microenvironment in Therapy-Induced Neovascularization of Glioblastoma. Biochem Physiol 2013;2:e121. [Crossref]
- Achyut BR, Arbab AS. Myeloid cell signatures in tumor microenvironment predicts therapeutic response in cancer. Onco Targets Ther 2016;9:1047-55. [PubMed]
- Achyut BR, Shankar A, Iskander AS, et al. Bone marrow derived myeloid cells orchestrate antiangiogenic resistance in glioblastoma through coordinated molecular networks. Cancer Lett 2015;369:416-26. [Crossref] [PubMed]
- Quail DF, Bowman RL, Akkari L, et al. The tumor microenvironment underlies acquired resistance to CSF-1R inhibition in gliomas. Science 2016;352:aad3018. [Crossref] [PubMed]
- Solito S, Marigo I, Pinton L, et al. Myeloid-derived suppressor cell heterogeneity in human cancers. Ann N Y Acad Sci 2014;1319:47-65. [Crossref] [PubMed]
- Gabrilovich DI, Nagaraj S. Myeloid-derived suppressor cells as regulators of the immune system. Nat Rev Immunol 2009;9:162-74. [Crossref] [PubMed]
- Bronte V, Brandau S, Chen SH, et al. Recommendations for myeloid-derived suppressor cell nomenclature and characterization standards. Nat Commun 2016;7:12150. [Crossref] [PubMed]
- Apolloni E, Bronte V, Mazzoni A, et al. Immortalized myeloid suppressor cells trigger apoptosis in antigen-activated T lymphocytes. J Immunol 2000;165:6723-30. [Crossref] [PubMed]
- Denies S, Combes F, Ghekiere C, et al. In vitro exploration of a myeloid-derived suppressor cell line as vehicle for cancer gene therapy. Cancer Gene Ther 2016. [Epub ahead of print]. [Crossref] [PubMed]
- Steding CE, Wu ST, Zhang Y, et al. The role of interleukin-12 on modulating myeloid-derived suppressor cells, increasing overall survival and reducing metastasis. Immunology 2011;133:221-38. [Crossref] [PubMed]
- Del Vecchio M, Bajetta E, Canova S, et al. Interleukin-12: biological properties and clinical application. Clin Cancer Res 2007;13:4677-85. [Crossref] [PubMed]
- Shimokawa T, Okumura K, Ra C. DNA induces apoptosis in electroporated human promonocytic cell line U937. Biochem Biophys Res Commun 2000;270:94-9. [Crossref] [PubMed]
- Znidar K, Bosnjak M, Cemazar M, et al. Cytosolic DNA Sensor Upregulation Accompanies DNA Electrotransfer in B16.F10 Melanoma Cells. Mol Ther Nucleic Acids 2016;5:e322. [Crossref]
- Zhang L, Morgan RA, Beane JD, et al. Tumor-infiltrating lymphocytes genetically engineered with an inducible gene encoding interleukin-12 for the immunotherapy of metastatic melanoma. Clin Cancer Res 2015;21:2278-88. [Crossref] [PubMed]
- Achyut BR, Shankar A, Iskander AS, et al. Chimeric Mouse model to track the migration of bone marrow derived cells in glioblastoma following anti-angiogenic treatments. Cancer Biol Ther 2016;17:280-90. [Crossref] [PubMed]
- Eisenstein S, Coakley BA, Briley-Saebo K, et al. Myeloid-derived suppressor cells as a vehicle for tumor-specific oncolytic viral therapy. Cancer Res 2013;73:5003-15. [Crossref] [PubMed]
- Chandra D, Jahangir A, Quispe-Tintaya W, et al. Myeloid-derived suppressor cells have a central role in attenuated Listeria monocytogenes-based immunotherapy against metastatic breast cancer in young and old mice. Br J Cancer 2013;108:2281-90. [Crossref] [PubMed]
- Dranoff G. Cytokines in cancer pathogenesis and cancer therapy. Nat Rev Cancer 2004;4:11-22. [Crossref] [PubMed]