TY - JOUR
T1 - Type I interferon subtypes differentially activate the anti-leukaemic function of natural killer cells
AU - Barnes, Samantha A.
AU - Audsley, Katherine M.
AU - Newnes, Hannah V.
AU - Fernandez, Sonia
AU - de Jong, Emma
AU - Waithman, Jason
AU - Foley, Bree
N1 - Funding Information:
This work was supported by the Australian Government Research Training Program Scholarship at The University of Western Australia and the Lions Cancer Institute Karen & Joshua Chinnery PhD Top Up Scholarship administered by Cancer Council WA (scholarships to SB and HN), the Richard Walter Gibbon Medical Research Scholarship and Rachel Kierath Top-Up Scholarship in Paediatric Cancer Research (scholarships to KA), and funding from the Government of Western Australia Department of Health, Cancer Council WA, Brady Cancer Support Foundation, and the Children’s Leukaemia and Cancer Research Foundation (research funding to BF).
Publisher Copyright:
Copyright © 2022 Barnes, Audsley, Newnes, Fernandez, de Jong, Waithman and Foley.
PY - 2022/11/24
Y1 - 2022/11/24
N2 - Natural killer (NK) cells have an intrinsic ability to detect and eliminate leukaemic cells. Cellular therapies using cytokine-activated NK cells have emerged as promising treatments for patients with advanced leukaemia. However, not all patients respond to current NK cell therapies, and thus improvements in efficacy are required. Type I interferons (IFN-I) are a family of potent immunomodulatory cytokines with a known ability to modulate NK cell responses against cancer. Although the human IFN-I family comprises 16 distinct subtypes, only IFNα2 has been widely explored as an anti-cancer agent. Here, we investigated the individual immunomodulatory effects each IFNα subtype and IFNβ had on NK cell functionality to determine whether a particular subtype confers enhanced effector activity against leukaemia. Importantly, IFNα14 and IFNβ were identified as superior activators of NK cell effector function in vitro. To test the ability of these subtypes to enhance NK cell activity in vivo, IFN-I stimulation was overlaid onto a standard ex vivo expansion protocol to generate NK cells for adoptive cell therapy. Interestingly, infusion of NK cells pre-activated with IFNα14, but not IFNβ, significantly prolonged survival in a preclinical model of leukaemia compared to NK cells expanded without IFN-I. Collectively, these results highlight the diverse immunomodulatory potencies of individual IFN-I subtypes and support further investigation into the use of IFNα14 to favourably modulate NK cells against leukaemia.
AB - Natural killer (NK) cells have an intrinsic ability to detect and eliminate leukaemic cells. Cellular therapies using cytokine-activated NK cells have emerged as promising treatments for patients with advanced leukaemia. However, not all patients respond to current NK cell therapies, and thus improvements in efficacy are required. Type I interferons (IFN-I) are a family of potent immunomodulatory cytokines with a known ability to modulate NK cell responses against cancer. Although the human IFN-I family comprises 16 distinct subtypes, only IFNα2 has been widely explored as an anti-cancer agent. Here, we investigated the individual immunomodulatory effects each IFNα subtype and IFNβ had on NK cell functionality to determine whether a particular subtype confers enhanced effector activity against leukaemia. Importantly, IFNα14 and IFNβ were identified as superior activators of NK cell effector function in vitro. To test the ability of these subtypes to enhance NK cell activity in vivo, IFN-I stimulation was overlaid onto a standard ex vivo expansion protocol to generate NK cells for adoptive cell therapy. Interestingly, infusion of NK cells pre-activated with IFNα14, but not IFNβ, significantly prolonged survival in a preclinical model of leukaemia compared to NK cells expanded without IFN-I. Collectively, these results highlight the diverse immunomodulatory potencies of individual IFN-I subtypes and support further investigation into the use of IFNα14 to favourably modulate NK cells against leukaemia.
KW - adoptive cell therapy
KW - immunotherapy
KW - interferon subtypes
KW - leukemia
KW - natural killer cells
UR - http://www.scopus.com/inward/record.url?scp=85143434108&partnerID=8YFLogxK
U2 - 10.3389/fimmu.2022.1050718
DO - 10.3389/fimmu.2022.1050718
M3 - Article
C2 - 36505400
AN - SCOPUS:85143434108
SN - 1664-3224
VL - 13
JO - Frontiers in Immunology
JF - Frontiers in Immunology
M1 - 1050718
ER -