Bibliographic Details
| Title: |
The DNA methyltransferase inhibitor, guadecitabine, targets tumor-induced myelopoiesis and recovers T cell activity to slow tumor growth in combination with adoptive immunotherapy in a mouse model of breast cancer |
| Authors: |
Andrea J. Luker, Laura J. Graham, Timothy M. Smith, Carmen Camarena, Matt P. Zellner, Jamie-Jean S. Gilmer, Sheela R. Damle, Daniel H. Conrad, Harry D. Bear, Rebecca K. Martin |
| Source: |
BMC Immunology, Vol 21, Iss 1, Pp 1-15 (2020) |
| Publisher Information: |
BMC, 2020. |
| Publication Year: |
2020 |
| Collection: |
LCC:Immunologic diseases. Allergy |
| Subject Terms: |
Myeloid derived suppressor cells, DNA methyltransferase inhibitor, Immunotherapy, T lymphocytes, Myelopoiesis, Immunologic diseases. Allergy, RC581-607 |
| More Details: |
Abstract Background Myeloid derived suppressor cells (MDSCs) present a significant obstacle to cancer immunotherapy because they dampen anti-tumor cytotoxic T cell responses. Previous groups, including our own, have reported on the myelo-depletive effects of certain chemotherapy agents. We have shown previously that decitabine increased tumor cell Class I and tumor antigen expression, increased ability of tumor cells to stimulate T lymphocytes, depleted tumor-induced MDSC in vivo and augmented immunotherapy of a murine mammary carcinoma. Results In this study, we expand upon this observation by testing a next-generation DNA methyltransferase inhibitor (DNMTi), guadecitabine, which has increased stability in the circulation. Using the 4 T1 murine mammary carcinoma model, in BALB/cJ female mice, we found that guadecitabine significantly reduces tumor burden in a T cell-dependent manner by preventing excessive myeloid proliferation and systemic accumulation of MDSC. The remaining MDSC were shifted to an antigen-presenting phenotype. Building upon our previous publication, we show that guadecitabine enhances the therapeutic effect of adoptively transferred antigen-experienced lymphocytes to diminish tumor growth and improve overall survival. We also show guadecitabine’s versatility with similar tumor reduction and augmentation of immunotherapy in the C57BL/6 J E0771 murine breast cancer model. Conclusions Guadecitabine depleted and altered MDSC, inhibited growth of two different murine mammary carcinomas in vivo, and augmented immunotherapeutic efficacy. Based on these findings, we believe the immune-modulatory effects of guadecitabine can help rescue anti-tumor immune response and contribute to the overall effectiveness of current cancer immunotherapies. |
| Document Type: |
article |
| File Description: |
electronic resource |
| Language: |
English |
| ISSN: |
1471-2172 |
| Relation: |
http://link.springer.com/article/10.1186/s12865-020-0337-5; https://doaj.org/toc/1471-2172 |
| DOI: |
10.1186/s12865-020-0337-5 |
| Access URL: |
https://doaj.org/article/8705275c0da24e8995eee5018ccbc1c7 |
| Accession Number: |
edsdoj.8705275c0da24e8995eee5018ccbc1c7 |
| Database: |
Directory of Open Access Journals |
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