Scientific Reports (Jul 2022)

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

  • Rae Hunter,
  • Kathleen J. Imbach,
  • Chengjing Zhou,
  • Jodi Dougan,
  • Jamie A. G. Hamilton,
  • Kevin Z. Chen,
  • Priscilla Do,
  • Ashley Townsel,
  • Greg Gibson,
  • Erik C. Dreaden,
  • Edmund K. Waller,
  • Karmella A. Haynes,
  • Curtis J. Henry,
  • Christopher C. Porter

DOI
https://doi.org/10.1038/s41598-022-16152-z
Journal volume & issue
Vol. 12, no. 1
pp. 1 – 13

Abstract

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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.