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
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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