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TNP-470 skews DC differentiation to Th1-stimulatory phenotypes and can serve as a novel adjuvant in a cancer vaccine.

ABSTRACT: Fumagillin is an antiangiogenic and antineoplastic fungal natural product, and TNP-470 is one of its most potent analogs. Decades of studies revealed that TNP-470 has potent anticancer activities via destruction of neovasculature. In stark contrast, TNP-470 has been reported to suppress lymphocyte proliferation, thereby limiting its clinical potentials. In an attempt to investigate whether the similar or opposite immunomodulatory effect of TNP-470 could act on myeloid cells, we found that TNP-470 potentiates the immunogenicity of dendritic cells (DCs) toward a phenotype with T helper cell type 1 (Th1)-stimulatory features. Using DC vaccine on a murine melanoma cancer model, the TNP-470-treated DC vaccine could significantly induce tumor-specific immunogenicity and substantially enhance tumor eradication when compared with vehicle-treated DC vaccine in a prophylactic setting. Enhanced tumor-specific immunogenicity and delayed tumor progression were observed in a therapeutic setting upon the TNP-470-treated DC vaccine. Our data showed that TNP-470 potentiates Toll-like receptor signaling, including NF-?B activation, in DCs to transcriptionally activate interleukin-12 production, thus inducing a Th1-immune response. Our current study uncovers a novel immune function of TNP-470 in DCs and redefines its role as a novel class of small molecule immune adjuvant in DC-based cancer vaccine given potentiation of DC immunogenicity is a major roadblock in DC vaccine development. Our study not only provides a novel adjuvant for ex vivo-cultured patient-specific DC vaccines for cancer treatment but also discovers the distinct immunostimulatory function of TNP-470 in DCs of myeloid lineage that differs from its immunosuppressive function in lymphoid cells.

SUBMITTER: Ho DH

PROVIDER: S-EPMC6058227 | biostudies-literature | 2018 Jul

REPOSITORIES: biostudies-literature

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TNP-470 skews DC differentiation to Th1-stimulatory phenotypes and can serve as a novel adjuvant in a cancer vaccine.

Ho Derek Hoi-Hang DH Wong Roger Hoi-Fung RH

Blood advances 20180701 14

Fumagillin is an antiangiogenic and antineoplastic fungal natural product, and TNP-470 is one of its most potent analogs. Decades of studies revealed that TNP-470 has potent anticancer activities via destruction of neovasculature. In stark contrast, TNP-470 has been reported to suppress lymphocyte proliferation, thereby limiting its clinical potentials. In an attempt to investigate whether the similar or opposite immunomodulatory effect of TNP-470 could act on myeloid cells, we found that TNP-47 ...[more]

PMID: 30012585

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Project description:Immunogenicity of cancer vaccines is impacted by adjuvants and schedule, but systematic assessments of their effects have not been performed. Montanide ISA-51, an incomplete Freund's adjuvant (IFA), is used in many vaccine trials, but concerns have been raised about negative effects in murine studies. We found in humans that IFA enhances systemic immune responses and that repeat vaccination at one site (same site vaccination (SSV)) creates tertiary lymphoid structures (TLS) in the vaccine site microenvironment (VSME). We hypothesized that vaccination with peptides+IFA+pICLC or SSV×3 with peptides in IFA would create an immunogenic milieu locally at the VSME, with activated dendritic cells (DC), TLS-associated chemokines and a Th1-dominant VSME. Biopsies of the VSME were obtained from participants on two clinical trials who were immunized with multiple melanoma peptides (MELITAC 12.1) in adjuvants comprising IFA and/or the TLR3-agonist pICLC. Biopsies were obtained either a week after one vaccine or a week after SSV×3. Controls included normal skin and skin injected with IFA without peptides. Gene expression analysis was performed by RNAseq. VSME samples were evaluated from 27 patients. One vaccine with peptides in pICLC+IFA enhanced expression of CD80, CD83, CD86 (p<0.01), CD40 and CD40L (p<0.0001) over normal skin; these effects were significantly enhanced for SSV with peptides+IFA. Vaccines containing pICLC increased expression of TBX21 (T-bet) but did not decrease GATA3 over normal skin, whereas SSV with peptides in IFA dramatically enhanced TBX21 and decreased GATA3, with high expression of IFNγ and STAT1. SSV with peptides in IFA also reduced arginase-1 (ARG1) expression and enhanced expression of TLR adapter molecules TICAM-1 (TRIF) and MYD88. Furthermore, SSV with IFA and peptides also enhanced expression of chemokines associated with TLS formation. These findings suggest that SSV with peptides in IFA enhances CD40L expression by CD4 T cells, supports a Th1 microenvironment, with accumulation of activated and mature DC. Increased expression of TLR adaptor proteins after SSV with peptides in IFA might implicate effects of the skin microbiome. Reduced ARG1 may reflect diminished suppressive myeloid activity in the VSME. (NCT00705640, NCT01585350).

Dataset Information

TNP-470 skews DC differentiation to Th1-stimulatory phenotypes and can serve as a novel adjuvant in a cancer vaccine.

Publications

TNP-470 skews DC differentiation to Th1-stimulatory phenotypes and can serve as a novel adjuvant in a cancer vaccine.

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