Epigenetic Therapy Promotes Dendritic Cell Differentiation in MDS

Our experience with immunotherapy in myeloid cancers suggests that understanding of immunologic milieu in these diseases is required to maximize the response to therapy.
Epigenetic Therapy Promotes Dendritic Cell Differentiation in MDS

One of the challenges facing the use of immunotherapy for the treatment of myelodysplastic syndromes (MDS) and other myeloid cancers in our incomplete understanding of the immunologic milieu. In a previous study, we found that a dendritic cell (DC) population marked by high-expression of CD141 (CD141Hi DC) was reduced in the peripheral blood of MDS patients (1).  In patients with solid tumors, the presence of CD141Hi DCs in the tumor microenvironment is necessary to generate and maintain anti-tumor immune responses (2). Based on our observations, we hypothesized a model in which MDS patients exhibit defective differentiation of DC-committed precursors, due in part to epigenetic mechanisms, which leads to decreased number of functional CD141Hi DCs.  This deficiency may hinder effective immune surveillance and potentially limit the response to immunotherapies under clinical development.

We tested this hypothesis by studying CD141Hi DC population in the bone marrow of a larger cohort of MDS patients (3). For these patients, the bone marrow is the tumor microenvironment. Overall, MDS patients showed a reduced number of CD141Hi DCs in their bone marrow. Patients with relatively fewer CD141Hi cDCs showed inferior overall survival. The decreased numbers of CD141Hi DCs were associated with fewer numbers of precursors committed to DC differentiation. The MDS DC precursors expressed lower levels of interferon regulatory factor-8 (IRF8), a master regulator of CD141Hi DC differentiation.  

We then tested whether it is possible to rescue CD141Hi DC differentiation by targeting lysine specific demethylase 1 (LSD1). LSD1 suppresses gene expression by removing (or “erasing”)  post-translational modifications of histones associated with transcriptionally-permissive chromatin. LSD1 inhibitors induce IRF8 expression and myeloid cell differentiation and are being tested in clinical trials for myeloid malignancies (4,5). We found that pharmacologic inhibition of LSD1 enhanced CD141Hi DC differentiation from MDS blast cells.

Our study highlights an approach to increase CD141Hi DCs in patients with MDS, such as LSD1 inhibition, which may further enhance response to immune therapies. There remain several important questions to be answered such as how increasing CD141Hi DCs impacts anti-tumor immune surveillance and overall survival in MDS. Determining the mechanisms that regulate CD141Hi DC function in MDS patients will be necessary to translate our results, as well as those from other groups, to the clinical benefit of our patients.

This post was written by Pragya Srivastava, Elizabeth Griffiths, and Michael Nemeth

1    Griffiths EA, Srivastava P, Matsuzaki J, Brumberger Z, Wang ES, Kocent J et al. NY-ESO-1 Vaccination in Combination with Decitabine Induces Antigen-Specific T-lymphocyte Responses in Patients with Myelodysplastic Syndrome. Clin Cancer Res 2018; 24: 1019–1029.
2    Wculek SK, Cueto FJ, Mujal AM, Melero I, Krummel MF, Sancho D. Dendritic cells in cancer immunology and immunotherapy. Nature Rev Immunol; 2019; 144:646–18.
3    Srivastava P, Tzetzo SL, Cortes Gomez E, Eng KH, Jani Sait SN, Kuechle JB et al. Inhibition of LSD1 in MDS Progenitors Restores Differentiation of CD141Hi Conventional Dendritic Cells. Leukemia. https://www.nature.com/articles/s41375-020-0765-5
4    Bell CC, Fennell KA, Chan Y-C, Rambow F, Yeung MM, Vassiliadis D et al. Targeting enhancer switching overcomes non-genetic drug resistance in acute myeloid leukaemia. Nat Comm 2019; 10: 2723.
5    Maes T, Mascaró C, Tirapu I, Estiarte A, Ciceri F, Lunardi S et al. ORY-1001, a Potent and Selective Covalent KDM1A Inhibitor, for the Treatment of Acute Leukemia. Cancer Cell 2018; 33: 495–511.

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