B-cell acute lymphoblastic leukemia promotes an immune suppressive microenvironment that can be overcome by IL-12

• Type of Material: Article
• Authors: Rae Hunter, Emory University; Kathleen J Imbach, Georgia Institute of Technology; Chengjing Zhou, Emory University; Jodi Dougan, Emory University; Jamie AG Hamilton, Emory University; Kevin Z Chen, Emory University; Priscilla Do, Emory University; Ashley Townsel, Emory University; Greg Gibson, Georgia Institute of Technology; Erik Dreaden, Emory University; Edmund Waller, Emory University; Karmella Haynes, Emory University; Curtis Henry, Emory University; Christopher Porter, Emory University
• Language: English
• Date: 2022-07-13
• Publisher: NATURE PORTFOLIO
• Publication Version: Final Published Version
• Copyright Statement: © The Author(s) 2022
• License: Creative Commons Attribution 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1038/s41598-022-16152-z
• Title of Journal or Parent Work: SCIENTIFIC REPORTS
• Volume: 12
• Issue: 1
• Start Page: 11870
• End Page: 11870
• Keywords: RECOMBINANT HUMAN INTERLEUKIN-12; Science & Technology; RESISTANCE; Science & Technology - Other Topics; Multidisciplinary Sciences; INSIGHTS; CANCER; CHILDREN
• Research Categories: Biology, General; Engineering, Biomedical; Health Sciences, Oncology

Abstract

Immunotherapies have revolutionized the treatment of B-cell acute lymphoblastic leukemia (B-ALL), but the duration of responses is still sub-optimal. We sought to identify mechanisms of immune suppression in B-ALL and strategies to overcome them. Plasma collected from children with B-ALL with measurable residual disease after induction chemotherapy showed differential cytokine expression, particularly IL-7, while single-cell RNA-sequencing revealed the expression of genes associated with immune exhaustion in immune cell subsets. We also found that the supernatant of leukemia cells suppressed T-cell function ex vivo. Modeling B-ALL in mice, we observed an altered tumor immune microenvironment, including compromised activation of T-cells and dendritic cells (DC). However, recombinant IL-12 (rIL-12) treatment of mice with B-ALL restored the levels of several pro-inflammatory cytokines and chemokines in the bone marrow and increased the number of splenic and bone marrow resident T-cells and DCs. RNA-sequencing of T-cells isolated from vehicle and rIL-12 treated mice with B-ALL revealed that the leukemia-induced increase in genes associated with exhaustion, including Lag3, Tigit, and Il10, was abrogated with rIL-12 treatment. In addition, the cytolytic capacity of T-cells co-cultured with B-ALL cells was enhanced when IL-12 and blinatumomab treatments were combined. Overall, these results demonstrate that the leukemia immune suppressive microenvironment can be restored with rIL-12 treatment which has direct therapeutic implications.