Intrinsic suppression of type I interferon production underlies the therapeutic efficacy of IL-15-producing natural killer cells in B-cell acute lymphoblastic leukemia

Abstract

BackgroundType I interferons (IFN-Is), secreted by hematopoietic cells, drive immune surveillance of solid tumors. However, the mechanisms of suppression of IFN-I-driven immune responses in hematopoietic malignancies including B-cell acute lymphoblastic leukemia (B-ALL) are unknown.MethodsUsing high-dimensional cytometry, we delineate the defects in IFN-I production and IFN-I-driven immune responses in high-grade primary human and mouse B-ALLs. We develop natural killer (NK) cells as therapies to counter the intrinsic suppression of IFN-I production in B-ALL.ResultsWe find that high expression of IFN-I signaling genes predicts favorable clinical outcome in patients with B-ALL, underscoring the importance of the IFN-I pathway in this malignancy. We show that human and mouse B-ALL microenvironments harbor an intrinsic defect in paracrine (plasmacytoid dendritic cell) and/or autocrine (B-cell) IFN-I production and IFN-I-driven immune responses. Reduced IFN-I production is sufficient for suppressing the immune system and promoting leukemia development in mice prone to MYC-driven B-ALL. Among anti-leukemia immune subsets, suppression of IFN-I production most markedly lowers the transcription of IL-15 and reduces NK-cell number and effector maturation in B-ALL microenvironments. Adoptive transfer of healthy NK cells significantly prolongs survival of overt ALL-bearing transgenic mice. Administration of IFN-Is to B-ALL-prone mice reduces leukemia progression and increases the frequencies of total NK and NK-cell effectors in circulation. Ex vivo treatment of malignant and non-malignant immune cells in primary mouse B-ALL microenvironments with IFN-Is fully restores proximal IFN-I signaling and partially restores IL-15 production. In B-ALL patients, the suppression of IL-15 is the most severe in difficult-to-treat subtypes with MYC overexpression. MYC overexpression promotes sensitivity of B-ALL to NK cell-mediated killing. To counter the suppressed IFN-I-induced IL-15 production in MYChighhuman B-ALL, we CRISPRa-engineered a novel human NK-cell line that secretes IL-15. CRISPRa IL-15-secreting human NK cells kill high-grade human B-ALL in vitro and block leukemia progression in vivo more effectively than NK cells that do not produce IL-15.ConclusionWe find that restoration of the intrinsically suppressed IFN-I production in B-ALL underlies the therapeutic efficacy of IL-15-producing NK cells and that such NK cells represent an attractive therapeutic solution for the problem of drugging MYC in high-grade B-ALL.

Single-cell transcriptome sequencing provides insight into multiple chemotherapy resistance in a patient with refractory DLBCL: a case report

“…We found that MYC+BCL2+ B cells can cause an inflammatory microenvironment with immunosuppressive characteristics through some immune inflammatory signaling pathways. This is consistent with the conclusion of recent studies, which showed that lymphoma cells with obvious proliferative characteristics have the potential to induce a ‘depleted’ microenvironment ( 32 – 34 ). The patient in this case was not only confirmed as a double-expressed patient by immunohistochemistry, but at the cellular level, we also identified a malignant B subgroup of “MYC+ BCL2+”, indicating high proliferation of B cells in the patient’s tumor.…”

Rare Drivers at Low Prevalence with High Cancer Effects in T-Cell and B-Cell Pediatric Acute Lymphoblastic Leukemia

“…Nonetheless, they can have a crucial—even primary—role in disease. Other mutations at low prevalence and even low effect may also be crucially important in a distinct co-occurring genetic context [ 45 , 46 ] or molecularly defined subtype [ 5 , 47 ]; for instance, the single-nucleotide mutations of CDKN2A in B-cell and T-cell ALL have a low estimate of effect ignoring context, but the high frequency of CDKN2A deletions and their co-occurrence with substitutions (3 out of 5 T-ALL patients with CDKN2A substitutions have the focal deletion of the other copy; among B-ALL patients, 4 out of 12) indicate a large selective epistatic effect. Prioritizing the investigation of these high-impact targets not only opens new avenues for potentially highly effective therapeutic targets but also provides valuable insights into the intricate mechanisms driving the disease, thereby advancing our understanding and ultimately leading to improvements in precision therapeutics.…”

B-cell precursor acute lymphoblastic leukemia elicits an interferon-α/βresponse in bone marrow-derived mesenchymal stroma

“… 39 , 40 However, increased IFN-related gene expression in MSC after contact with leukemic cells may also reflect an anti-leukemic response of MSC in the tumor microenvironment to attract other immune cells. 31 , 41 , 42 A recent study by Kumar et al showed that reduced production of IFNα/β, leading to decreased NK-cell surveillance, promotes development of B-ALL in vivo. 42 Restoring this IFNα/β production allows for NK effector cells to reduce leukemia progression in mice that are prone to MYC-driven B-ALL.…”

“… 31 , 41 , 42 A recent study by Kumar et al showed that reduced production of IFNα/β, leading to decreased NK-cell surveillance, promotes development of B-ALL in vivo. 42 Restoring this IFNα/β production allows for NK effector cells to reduce leukemia progression in mice that are prone to MYC-driven B-ALL. In high-risk acute myeloid leukemia, IFNα/β administration after hematopoietic stem cell transplantation may be effective in preventing relapse.…”