Alarmin IL-33 Acts as an Immunoadjuvant to Enhance Antigen-Specific Tumor Immunity

• Published in: Cancer research (Chicago, Ill.) Ill.), 2014-03, Vol.74 (6), p.1789-1800
• Main Authors: VILLARREAL, Daniel O, WISE, Megan C, WALTERS, Jewell N, REUSCHEL, Emma L, MIN JOUNG CHOI, OBENG-ADJEI, Nyamekye, JIAN YAN, MORROW, Matthew P, WEINER, David B
• Format: Article
• Language: English
• Subjects: Adjuvants, Immunologic - physiology; Animals; Antineoplastic agents; Biological and medical sciences; Cancer Vaccines; CD4-Positive T-Lymphocytes - immunology; CD8-Positive T-Lymphocytes - immunology; Cell Line, Tumor; Female; Human papillomavirus 16 - immunology; Humans; Immunity, Humoral; Immunotherapy; Interferon-gamma - metabolism; Interleukin-33; Interleukins - physiology; Medical sciences; Mice; Mice, Inbred C57BL; Multiple tumors. Solid tumors. Tumors in childhood (general aspects); Neoplasm Transplantation; Neoplasms - immunology; Neoplasms - therapy; Neoplasms - virology; Papillomavirus Infections - immunology; Papillomavirus Infections - therapy; Pharmacology. Drug treatments; Tumors
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/0008-5472.can-13-2729

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.