Single-Cell Multiomics Reveals Clonal T-Cell Expansions and Exhaustion in Blastic Plasmacytoid Dendritic Cell Neoplasm.

Erica A K Depasquale,Andrew A Lane,Martin A Villanueva,Sary F Aranki,Peter Van Galen,Gabriel K Griffin,Alex K Shalek,Jenny Noel,Hari R Mallidi,Marina Ainciburu,Jonathan Good,Charles P Couturier,Daniel Ssozi

doi:10.3389/fimmu.2022.809414

Abstract

The immune system represents a major barrier to cancer progression, driving the evolution of immunoregulatory interactions between malignant cells and T-cells in the tumor environment. Blastic plasmacytoid dendritic cell neoplasm (BPDCN), a rare acute leukemia with plasmacytoid dendritic cell (pDC) differentiation, provides a unique opportunity to study these interactions. pDCs are key producers of interferon alpha (IFNA) that play an important role in T-cell activation at the interface between the innate and adaptive immune system. To assess how uncontrolled proliferation of malignant BPDCN cells affects the tumor environment, we catalog immune cell heterogeneity in the bone marrow (BM) of five healthy controls and five BPDCN patients by analyzing 52,803 single-cell transcriptomes, including 18,779 T-cells. We test computational techniques for robust cell type classification and find that T-cells in BPDCN patients consistently upregulate interferon alpha (IFNA) response and downregulate tumor necrosis factor alpha (TNFA) pathways. Integrating transcriptional data with T-cell receptor sequencing via shared barcodes reveals significant T-cell exhaustion in BPDCN that is positively correlated with T-cell clonotype expansion. By highlighting new mechanisms of T-cell exhaustion and immune evasion in BPDCN, our results demonstrate the value of single-cell multiomics to understand immune cell interactions in the tumor environment.

Highlights

Innovations in immuno-oncology, such as immune checkpoint blockade (ICB) therapy, have transformed cancer medicine
Bone marrow aspirate was collected from 5 patients with blastic plasmacytoid dendritic cell neoplasm (BPDCN) who consented to an excess sample banking and sequencing protocol that covered all study procedures and was approved by the Institutional Review Board (IRB) of the Dana-Farber/Harvard Cancer Consortium
Scoring individual CD8+ Memory T-cells for the tumor necrosis factor alpha (TNFA) gene signature showed significant reductions in Blastic plasmacytoid dendritic cell neoplasm (BPDCN) (P = 0.0159, Wilcoxon signed rank test, Figure 3C). These results demonstrate that T/natural killer (NK)-cells in BPDCN exhibit consistent gene expression changes compared to healthy control cells, including increased response to the pDCrelated cytokine Interferon alpha (IFNA) and decreased TNFA signaling

Summary

Introduction

Innovations in immuno-oncology, such as immune checkpoint blockade (ICB) therapy, have transformed cancer medicine. ICB and CAR-T cells have led to improved outcomes in various solid tumors and B-cell malignancies, respectively [1], these methods have been less successful in myeloid leukemias than in other cancers. Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is an aggressive form of acute leukemia with few effective therapies that provides a unique opportunity to study IFN dysregulation in cancer. BPDCN is characterized by uncontrolled proliferation of transformed plasmacytoid dendritic cells (pDCs), specialized immune cells that link the innate and adaptive immune systems through the secretion of Type I interferons, including IFNA, during viral infection [10]. An effective immune response relies on the interaction between healthy innate and adaptive immune systems, which is critical for immunotherapy and may be impacted by IFNA-producing pDCs

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Results

Conclusion