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
Autor: | Andrea J. Luker, Daniel H. Conrad, Jamie-Jean S. Gilmer, Harry D. Bear, Rebecca K. Martin, Matt P. Zellner, Timothy M. Smith, Laura Graham, Carmen Camarena, Sheela R. Damle |
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Rok vydání: | 2019 |
Předmět: |
lcsh:Immunologic diseases. Allergy
T cell medicine.medical_treatment Immunology T lymphocytes Decitabine Antineoplastic Agents Breast Neoplasms DNA methyltransferase inhibitor Lymphocyte Activation Immunotherapy Adoptive 03 medical and health sciences Mice 0302 clinical medicine Cancer immunotherapy Cell Line Tumor medicine Cytotoxic T cell Animals Humans DNA Modification Methylases Cell Proliferation Myelopoiesis Mice Inbred BALB C business.industry Myeloid-Derived Suppressor Cells Cancer Immunotherapy medicine.disease Combined Modality Therapy Tumor antigen 3. Good health Mice Inbred C57BL medicine.anatomical_structure 030220 oncology & carcinogenesis Myeloid derived suppressor cells Myeloid-derived Suppressor Cell Cancer research Azacitidine Female business lcsh:RC581-607 030215 immunology medicine.drug T-Lymphocytes Cytotoxic Research Article |
Zdroj: | BMC Immunology BMC Immunology, Vol 21, Iss 1, Pp 1-15 (2020) |
ISSN: | 1471-2172 |
Popis: | 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. |
Databáze: | OpenAIRE |
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