Epigenetic Silencing of Immune-Checkpoint Receptors in Bone Marrow- Infiltrating T Cells in Acute Myeloid Leukemia.

Radpour, Ramin; Stucki, Miriam; Riether, Carsten; Ochsenbein, Adrian F. (2021). Epigenetic Silencing of Immune-Checkpoint Receptors in Bone Marrow- Infiltrating T Cells in Acute Myeloid Leukemia. Frontiers in oncology, 11, p. 663406. Frontiers Research Foundation 10.3389/fonc.2021.663406

[img]
Preview
Text
fonc-11-663406.pdf - Published Version
Available under License Creative Commons: Attribution (CC-BY).

Download (17MB) | Preview

Background

Immune-checkpoint (IC) inhibitors have revolutionized the treatment of multiple solid tumors and defined lymphomas, but they are largely ineffective in acute myeloid leukemia (AML). The reason why especially PD1/PD-L1 blocking agents are not efficacious is not well-understood but it may be due to the contribution of different IC ligand/receptor interactions that determine the function of T cells in AML.

Methods

To analyze the interactions of IC ligands and receptors in AML, we performed a comprehensive transcriptomic analysis of FACS-purified leukemia stem/progenitor cells and paired bone marrow (BM)-infiltrating CD4+ and CD8+ T cells from 30 patients with AML. The gene expression profiles of activating and inhibiting IC ligands and receptors were correlated with the clinical data. Epigenetic mechanisms were studied by inhibiting the histone deacetylase with valproic acid or by gene silencing of PAC1.

Results

We observed that IC ligands and receptors were mainly upregulated in leukemia stem cells. The gene expression of activating IC ligands and receptors correlated with improved prognosis and vice versa. In contrast, the majority of IC receptor genes were downregulated in BM-infiltrating CD8+ T cells and partially in CD4+ T cells, due to pathological chromatin remodeling via histone deacetylation. Therefore, treatment with histone deacetylase inhibitor (HDACi) or silencing of PAC1, as a T cell-specific epigenetic modulator, significantly increased the expression of IC receptors and defined effector molecules in CD8+ T cells.

Conclusions

Our results suggest that CD8+ T cells in AML are dysfunctional mainly due to pathological epigenetic silencing of activating IC receptors rather than due to signaling by immune inhibitory IC receptors, which may explain the limited efficacy of antibodies that block immune-inhibitory ICs in AML.

Item Type:

Journal Article (Original Article)

Division/Institute:

04 Faculty of Medicine > Department of Haematology, Oncology, Infectious Diseases, Laboratory Medicine and Hospital Pharmacy (DOLS) > Clinic of Medical Oncology
04 Faculty of Medicine > Pre-clinic Human Medicine > BioMedical Research (DBMR) > DBMR Forschung Mu35 > Forschungsgruppe Tumor-Immunologie
04 Faculty of Medicine > Pre-clinic Human Medicine > BioMedical Research (DBMR) > DBMR Forschung Mu35 > Forschungsgruppe Tumor-Immunologie

UniBE Contributor:

Radpour, Ramin; Riether, Carsten and Ochsenbein, Adrian

Subjects:

600 Technology > 610 Medicine & health

ISSN:

2234-943X

Publisher:

Frontiers Research Foundation

Language:

English

Submitter:

Rebeka Gerber

Date Deposited:

28 Sep 2021 12:04

Last Modified:

03 Oct 2021 03:01

Publisher DOI:

10.3389/fonc.2021.663406

PubMed ID:

34017684

Uncontrolled Keywords:

CD4+ T cell CD8+ T cell acute myeloid leukemia epigenetics (chromatin remodelling) histone (de)acetylation immune-checkpoints immunotherapy leukemia stem cell (LSC)

BORIS DOI:

10.48350/159241

URI:

https://boris.unibe.ch/id/eprint/159241

Actions (login required)

Edit item Edit item
Provide Feedback