Dataset Information

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.

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.

SUBMITTER: Luker AJ

PROVIDER: S-EPMC7045411 | biostudies-literature | 2020 Feb

REPOSITORIES: biostudies-literature

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Publications

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.

Luker Andrea J AJ Graham Laura J LJ Smith Timothy M TM Camarena Carmen C Zellner Matt P MP Gilmer Jamie-Jean S JS Damle Sheela R SR Conrad Daniel H DH Bear Harry D HD Martin Rebecca K RK

BMC immunology 20200227 1

<h4>Background</h4>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 im ...[more]

PMID: 32106810

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Project description:There is an urgent need to develop more effective therapies for hepatocellular carcinoma (HCC) because of its aggressiveness. Guadecitabine (SGI-110) is a second-generation DNA methyltransferase inhibitor (DNMTi), which is currently in clinical trials for HCC and shows greater stability and performance over first-generation DNMTis. In order to identify potential therapeutic targets of SGI-110 for clinical trials, HCC cell lines (SNU398, HepG2, and SNU475) were used to evaluate the effects of transient SGI-110 treatment by an integrative analysis of DNA methylation, nucleosome accessibility, gene expression profiles, and its clinical relevance by comparison to The Cancer Genome Atlas (TCGA) HCC clinical data. Each HCC cell line represents a different DNA methylation subtype of primary HCC tumors based on TCGA data. After SGI-110 treatment, all cell lines were sensitive to SGI-110 with prolonged antiproliferation effects. Expression of up-regulated genes, including tumor suppressors, was positively correlated with nucleosome accessibility and negatively correlated with gene promoter DNA methylation. Alternatively, expression of down-regulated genes, such as oncogenes, was negatively correlated with nucleosome accessibility and positively correlated with gene body DNA methylation. SGI-110 can also act as a dual inhibitor to down-regulate polycomb repressive complex 2 (PRC2) genes by demethylating their gene bodies, resulting in reactivation of PRC2 repressed genes without involvement of DNA methylation. Furthermore, it can up-regulate endogenous retroviruses to reactivate immune pathways. Finally, about 48% of frequently altered genes in primary HCC tumors can be reversed by SGI-110 treatment. CONCLUSION:Our integrative analysis has successfully linked the antitumor effects of SGI-110 to detailed epigenetic alterations in HCC cells, identified potential therapeutic targets, and provided a rationale for combination treatments of SGI-110 with immune checkpoint therapies.

Dataset Information

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.

Background

Results

Conclusions

Publications

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.

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