DNA methyltransferase inhibition promotes recruitment of myeloid-derived suppressor cells to the tumor microenvironment through induction of tumor cell-intrinsic interleukin-1

Traynor, Sofie; Terp, Mikkel Green; Nielsen, Aaraby Yoheswaran; Guldberg, Per; Jakobsen, Mie; Pedersen, Pernille Gejl; Gammelgaard, Odd L.; Pedersen, Christina Gundgaard; Pedersen, Mathilde; Rattenborg, Sofie; Ditzel, Henrik J.; Gjerstorff, Morten F.

doi:10.1016/j.canlet.2022.215982

Cited by 9 publications

(11 citation statements)

References 54 publications

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“…However, when focusing on specific cell types that are present and functional, these models can be highly suitable to investigate how tumor intrinsic responses to various therapies affect the TME. For instance, using PDX models, we have recently shown that a potential unfavorable effect of DNA methyltransferase inhibitors leads to increased IL-1 expression that supports the recruitment of monocytic myeloid-derived suppressor cells to the TME [ 42 ]. Functionally, using immunodeficient nude mice with MDA-MB-231 breast cancer cells, it has been demonstrated that MDSCs expand in breast cancer bone metastases and induce bone destruction [ 43 ].…”

Section: Discussionmentioning

confidence: 99%

PDX Models: A Versatile Tool for Studying the Role of Myeloid-Derived Suppressor Cells in Breast Cancer

Gjerstorff

Traynor

Gammelgaard

et al. 2022

Cancers

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The pivotal role of myeloid-derived suppressive cells (MDSCs) in cancer has become increasingly apparent over the past few years. However, to fully understand how MDSCs can promote human tumor progression and to develop strategies to target this cell type, relevant models that closely resemble the clinical complexity of human tumors are needed. Here, we show that mouse MDSCs of both the monocytic (M-MDCS) and the granulocytic (PMN-MDSC) lineages are recruited to human breast cancer patient-derived xenograft (PDX) tumors in mice. Transcriptomic analysis of FACS-sorted MDSC-subpopulations from the PDX tumors demonstrated the expression of several MDSC genes associated with both their mobilization and immunosuppressive function, including S100A8/9, Ptgs2, Stat3, and Cxcr2, confirming the functional identity of these cells. By combining FACS analysis, RNA sequencing, and immune florescence, we show that the extent and type of MDSC infiltration depend on PDX model intrinsic factors such as the expression of chemokines involved in mobilizing and recruiting tumor-promoting MDSCs. Interestingly, MDSCs have been shown to play a prominent role in breast cancer metastasis, and in this context, we demonstrate increased recruitment of MDSCs in spontaneous PDX lung metastases compared to the corresponding primary PDX tumors. We also demonstrate that T cell-induced inflammation enhances the recruitment of MDSC in experimental breast cancer metastases. In conclusion, breast cancer PDX models represent a versatile tool for studying molecular mechanisms that drive myeloid cell recruitment to primary and metastatic tumors and facilitate the development of innovative therapeutic strategies targeting these cells.

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Section: Discussionmentioning

confidence: 99%

PDX Models: A Versatile Tool for Studying the Role of Myeloid-Derived Suppressor Cells in Breast Cancer

Gjerstorff

Traynor

Gammelgaard

et al. 2022

Cancers

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“…Functioning as nucleoside analogs, these inhibitors integrate into DNA, leading to DNA hypomethylation ( Giri and Aittokallio, 2019 ). At therapeutic doses, they primarily exhibit a cytostatic effect, enabling the reactivation of previously silenced genes ( Traynor et al, 2023 ). Additionally, compounds like guadecitabine and CC-486 (oral azacitidine) are being evaluated in clinical trials for various conditions but have not yet been approved by the FDA ( Ochoa et al, 2023 ).…”

Section: During Cancer Treatmentmentioning

confidence: 99%

“…Current research focuses on developing non-nucleoside DNMT inhibitors with minimal off-target effects and enhanced specificity. Experimental compounds, including non-nucleoside analogs, are under investigation for their ability to more selectively block DNMT activity and reactivate tumor suppressor genes ( Traynor et al, 2023 ).…”

Section: During Cancer Treatmentmentioning

confidence: 99%

The pharmacoepigenetic paradigm in cancer treatment

Ocaña-Paredes,

Rivera-Orellana,

Ramírez-Sánchez

et al. 2024

Front. Pharmacol.

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Epigenetic modifications, characterized by changes in gene expression without altering the DNA sequence, play a crucial role in the development and progression of cancer by significantly influencing gene activity and cellular function. This insight has led to the development of a novel class of therapeutic agents, known as epigenetic drugs. These drugs, including histone deacetylase inhibitors, histone acetyltransferase inhibitors, histone methyltransferase inhibitors, and DNA methyltransferase inhibitors, aim to modulate gene expression to curb cancer growth by uniquely altering the epigenetic landscape of cancer cells. Ongoing research and clinical trials are rigorously evaluating the efficacy of these drugs, particularly their ability to improve therapeutic outcomes when used in combination with other treatments. Such combination therapies may more effectively target cancer and potentially overcome the challenge of drug resistance, a significant hurdle in cancer therapy. Additionally, the importance of nutrition, inflammation control, and circadian rhythm regulation in modulating drug responses has been increasingly recognized, highlighting their role as critical modifiers of the epigenetic landscape and thereby influencing the effectiveness of pharmacological interventions and patient outcomes. Epigenetic drugs represent a paradigm shift in cancer treatment, offering targeted therapies that promise a more precise approach to treating a wide spectrum of tumors, potentially with fewer side effects compared to traditional chemotherapy. This progress marks a step towards more personalized and precise interventions, leveraging the unique epigenetic profiles of individual tumors to optimize treatment strategies.

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“…DNMT inhibition stimulates the recruitment of MDSCs to TME, dampening antitumor immunity. 655 Besides the tumor-intrinsic mechanisms, low chemical stability and poor pharmacokinetic properties of the nucleoside DNMT inhibitors also account for the limited clinical efficacy.…”

Section: Targeting Methylation For Therapymentioning

confidence: 99%

Methylation across the central dogma in health and diseases: new therapeutic strategies

Liu,

Zhao,

et al. 2023

Sig Transduct Target Ther

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The proper transfer of genetic information from DNA to RNA to protein is essential for cell-fate control, development, and health. Methylation of DNA, RNAs, histones, and non-histone proteins is a reversible post-synthesis modification that finetunes gene expression and function in diverse physiological processes. Aberrant methylation caused by genetic mutations or environmental stimuli promotes various diseases and accelerates aging, necessitating the development of therapies to correct the disease-driver methylation imbalance. In this Review, we summarize the operating system of methylation across the central dogma, which includes writers, erasers, readers, and reader-independent outputs. We then discuss how dysregulation of the system contributes to neurological disorders, cancer, and aging. Current small-molecule compounds that target the modifiers show modest success in certain cancers. The methylome-wide action and lack of specificity lead to undesirable biological effects and cytotoxicity, limiting their therapeutic application, especially for diseases with a monogenic cause or different directions of methylation changes. Emerging tools capable of site-specific methylation manipulation hold great promise to solve this dilemma. With the refinement of delivery vehicles, these new tools are well positioned to advance the basic research and clinical translation of the methylation field.

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DNA methyltransferase inhibition promotes recruitment of myeloid-derived suppressor cells to the tumor microenvironment through induction of tumor cell-intrinsic interleukin-1

Cited by 9 publications

References 54 publications

PDX Models: A Versatile Tool for Studying the Role of Myeloid-Derived Suppressor Cells in Breast Cancer

PDX Models: A Versatile Tool for Studying the Role of Myeloid-Derived Suppressor Cells in Breast Cancer

The pharmacoepigenetic paradigm in cancer treatment

Methylation across the central dogma in health and diseases: new therapeutic strategies

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