Activated natural killer cells predict poor clinical prognosis in high-risk B- and T-cell acute lymphoblastic leukemia

Abstract

B- and T- cell acute lymphoblastic leukemia (B/T-ALL) may be refractory or recur after therapy by suppressing host anti-cancer immune surveillance mediated specifically by natural killer (NK) cells. We delineated the phenotypic and functional defects in NK cells of high-risk B/T-ALL patients using mass, flow, and in silico cytometry, with the goal of further elucidating the role of NK cells in sustaining ALL regression. We found that, compared to normal counterparts, NK cells in B/T-ALL patients are less cytotoxic, but exhibit an activated signature characterized by high CD56, high CD69, production of activated NK-origin cytokines, and calcium signaling. We demonstrated that defective maturation of NK cells into cytotoxic effectors prevents NK cells of ALL patients from lysing NK-sensitive targets as efficiently as normal NK cells. Additionally, we showed that NK cells in ALL are exhausted, which is likely caused by their chronic activation. We found that increased frequencies of activated cytokine-producing NK cells are associated with increased disease severity and independently predict poor clinical outcome in ALL patients. Our studies highlight the benefits of developing NK cell profiling as a diagnostic tool to predict clinical outcome in patients with ALL and underscore the clinical potential of allogeneic NK infusions to prevent ALL recurrence.

Natural Killer Cells in the Malignant Niche of Multiple Myeloma

“…Similar to what was published by Pazina et al, overall NK cell numbers and cytotoxic abilities are reduced in B/T-ALL patients as a result of CD56bright CD16-cytokine-producing stage 4 accumulation. In this study, high numbers of cytokine CD56bright CD16-cells were also associated with poor prognosis (166). The accumulation of CD56bright CD16-subset and lower total frequencies of NK cells in the BM reflect that NK cell lineage differentiation is impaired during the progression of hematological malignancies.…”

Generation and validation of CRISPR-engineered human natural killer cell lines for research and therapeutic applications

“…Natural killer (NK) cells are innate immune cells that protect against viral infections ( Strauss-Albee and Blish, 2016 ) and development of cancers ( Cerwenka and Lanier, 2001 ). NK cell-mediated immune surveillance is defective in infections and cancers for various reasons including NK cell exhaustion, defective homeostasis, and impaired NK cytotoxicity ( Duault et al., 2021 ; Wilk et al., 2021 ). Our overall goal is to develop therapeutic NK cells which are functional and evade exhaustion through CRISPR-based genetic manipulation.…”

Natural Killer Cell-Mediated Immunotherapy for Leukemia

“…A study looking at NK cell activity in B-and T-ALL patients showed that numbers were significantly decreased in both the bone marrow and peripheral blood [103]. B-ALL NK cells were shown to have significantly decreased cytotoxic capabilities compared to NK cells from healthy donors when killing assays were employed with ALL sensitive leukemia cells, indicating an immunosuppressed phenotype.…”