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

Abstract

Interleukin 33 (IL-33) has emerged as a cytokine that can exhibit pleiotropic properties. Here we examine IL-33 for its immunoadjuvant effects in an HPV-associated cancer immune therapy model in which cell-mediated immunity is critical for protection. It is known that two biologically active forms of IL-33 exist: full-length IL-33 and mature IL-33. The potential ability of both isoforms to act as vaccine adjuvants to influence the CD4 Th1 and CD8 T cell immune responses has not been well defined. We show that both isoforms of IL-33 are capable of enhancing potent antigen (Ag)-specific effector and memory T cell immunity in vivo in a DNA vaccine setting. We also show that while both forms of IL-33 drove robust IFN-γ responses, neither form drove high secretion of IL-4 or any elevation of IgE levels. Moreover, both isoforms augmented vaccine-induced Ag-specific polyfunctional CD4+ and CD8+ T cell responses, with a large proportion of CD8+ T cells undergoing cytolytic plurifunctional degranulation. Therapeutic studies indicated that established TC-1-bearing mice undergo rapid and complete regression after therapeutic vaccination with both IL-33 adjuvant isoforms used in conjunction with an HPV DNA vaccine. Furthermore, using the P14 transgenic mouse model, we show that IL-33 can significantly expand the magnitude of Ag-specific CD8+ T cell responses and elicit bonafide effector-memory CD8+ T cells. Overall, the data suggests the potential use of these two IL-33 isoforms as immunoadjuvant candidates in future vaccination against other pathogens and in the context of anti-tumor immune-based therapy.

Intratumorally Establishing Type 2 Innate Lymphoid Cells Blocks Tumor Growth

“…DNA vaccination with IL-33 adjuvants in conjugation with a human papilloma virus DNA vaccine is highly effective for regressing established tumors, probably by enhancing a tumor Ag-specific T cell response (12). Similar mechanisms, such as the IL-33-induced increase in IFN-g and perforin effector activities induced by NK cells and CD8 + T cells, act on eradicating IL-33-secreting tumors (13).…”

“…Three studies have provided evidence supporting involvement of IL-33 in antitumor immune responses, that is, transgenic expression, injection as a vaccine adjuvant, or overexpression in tumor cells of IL-33, and increased antitumor immunity by promoting CTL responses to tumor cells (11)(12)(13). However, it is unknown whether type 2 innate lymphoid cells (ILC2s), which respond vigorously to IL-33, are involved in IL-33-mediated antitumor responses.…”

Multivalent TB vaccines targeting the esx gene family generate potent and broad cell-mediated immune responses superior to BCG

“…In addition, we have reported on the use of genetic adjuvants to further enhance induced T cell immune responses in both preclinical as well as clinical studies. [55][56][57] Such combination studies would likely be important. Future studies should also evaluate this vaccine as part of a BCG prime boost strategy in protection studies.…”

IL-33 delays metastatic peritoneal cancer progression inducing an allergic microenvironment

“…8 Depending on its context, IL-33 has been reported to promote either Th1 9,10 or Th2 like immunity. 8 We have previously reported that IL-33 can be used as an immunoadjuvant to enhance DNA vaccine induced anti-tumor immunity by enhancing a Th1 response as an adjuvant in the periphery, particularly when expressed in muscle.…”

“…8 We have previously reported that IL-33 can be used as an immunoadjuvant to enhance DNA vaccine induced anti-tumor immunity by enhancing a Th1 response as an adjuvant in the periphery, particularly when expressed in muscle. 9 However, as ovarian cancer is often restricted to the peritoneal cavity, which is subject to heightened immunosurveilance, we hypothesized that IL-33 alone may promote a local immune response that could impact the prognosis of advanced ovarian cancer.…”