Alarmin IL-33 acts as an immunoadjuvant to enhance antigen-specific tumor immunity.
Studies of interleukin (IL)-33 reveal a number of pleiotropic properties. Here, we report that IL-33 has immunoadjuvant effects in a human papilloma virus (HPV)-associated model for cancer immunotherapy where cell-mediated immunity is critical for protection. Two biologically active isoforms of IL-33 exist that are full-length or mature, but the ability of either isoform to function as a vaccine adjuvant that influences CD4 T helper 1 or CD8 T-cell immune responses is not defined. We showed that both IL-33 isoforms are capable of enhancing potent antigen-specific effector and memory T-cell immunity in vivo in a DNA vaccine setting. In addition, although both IL-33 isoforms drove robust IFN-γ responses, neither elevated secretion of IL-4 or immunoglobulin E levels. Further, both isoforms augmented vaccine-induced antigen-specific polyfunctional CD4(+) and CD8(+) T-cell responses, with a large proportion of CD8(+) T cells undergoing plurifunctional cytolytic degranulation. Therapeutic studies indicated that vaccination with either IL-33 isoform in conjunction with an HPV DNA vaccine caused rapid and complete regressions in vivo. Moreover, IL-33 could expand the magnitude of antigen-specific CD8(+) T-cell responses and elicit effector-memory CD8(+) T cells. Taken together, our results support the development of these IL-33 isoforms as immunoadjuvants in vaccinations against pathogens, including in the context of antitumor immunotherapy.
Authors' Affiliations: Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia; Inovio Pharmaceuticals, Inc., Blue Bell, Pennsylvania; and Korea Food and Drug Administration, Osong-eup, Cheongwon-gun, Chungcheongbuk-do, Korea.
Daniel O
DO
Villarreal
Megan C
MC
Wise
Jewell N
JN
Walters
Emma L
EL
Reuschel
Min Joung
MJ
Choi
Nyamekye
N
Obeng-Adjei
Jian
J
Yan
Matthew P
MP
Morrow
David B
DB
Weiner
D000276:Adjuvants, Immunologic / Q000502:physiology*; D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D019496:Cancer Vaccines; D045744:Cell Line, Tumor; D005260:Female; D052162:Human papillomavirus 16 / Q000276:immunology; D006801:Humans; D056724:Immunity, Humoral; D007167:Immunotherapy; D007371:Interferon-gamma / Q000378:metabolism; D000067596:Interleukin-33; D007378:Interleukins / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D009368:Neoplasm Transplantation; D009369:Neoplasms / Q000276:immunology* / Q000628:therapy / Q000821:virology; D030361:Papillomavirus Infections / Q000276:immunology* / Q000628:therapy
D000276:Adjuvants, Immunologic; D019496:Cancer Vaccines; C506536:IL33 protein, human; D000067596:Interleukin-33; D007378:Interleukins; D007371:Interferon-gamma