Noncoding RNA danger motifs bridge innate and adaptive immunity and are potent adjuvants for vaccination

Wang, Lilin; Smith, Dan J.; Bot, Simona; Dellamary, Luis; Bloom, Amy; Bot, Adrian

doi:10.1172/jci0215536

Cited by 58 publications

(35 citation statements)

References 25 publications

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“…2D and 4A), the CL1 cells disappeared very rapidly. In an attempt to increase the antitumor response by CL1 cells, mice were treated with poly(I:C) in addition to IL-2c (37,38). This successfully induced the eradication of the tumors (Fig.…”

Section: Discussionmentioning

confidence: 99%

Adjuvants targeting innate and adaptive immunity synergize to enhance tumor immunotherapy

Verdeil

Marquardt²,

Surh³

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

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Because of mechanisms of self-tolerance, many tumor-specific CD8 T cells exhibit low avidity for tumor antigens and would benefit from strategies that enhance their numbers and effector function. Here we demonstrate that the combined use of two different types of immune adjuvants, one that directly targets the CD8 cell, IL-2/anti-IL-2 mAb complexes, and one that targets the innate immune system, poly(I:C), can achieve this goal. Provision of IL-2/mAb complexes was found to enhance the activation and effector function of low-avidity tumor-specific T cells, yet this was insufficient to achieve tumor eradication. The addition of poly(I:C) further increased the accumulation of granzyme B-expressing effectors within the tumor and resulted in tumor eradication. This strategy presents many of the benefits of whole-body irradiation, including the provision of high levels of homeostatic cytokines, enhanced expansion of effector cells relative to regulatory T cells, and provision of inflammatory cytokines, and is therefore likely to serve as a strategy for both tumor vaccines and adoptive immunotherapy of cancer.CD8 T cells ͉ cytokine complexes ͉ interleukin-2 ͉ TLR ͉ tumor immunity A ctivation of T cells by chronically expressed tumor antigens results in tolerance through deletion, anergy, and immunoregulation (1-3). As a result, residual tumor-specific T cells are generally of low avidity or anergic (4, 5). A goal of cancer immunotherapy is to identify immune adjuvants that can activate and amplify these residual low-avidity tumor-reactive T cells. Recent studies have revealed that cytokines of the common ␥ chain receptor family, including IL-2, IL-4, IL-7, and IL-15, promote expansion and survival of CD8 T cells (6). Their receptor is composed of the common ␥ chain (CD132), the ␤ chain (CD122) for IL-2 and IL-15, and a cytokine-specific receptor subunit, IL-2R␣ (CD25), IL-4R␣ (CD124), and IL-7R␣ (CD127). Regulated expression of the specific receptor subunits by different T cell subsets determines which cytokines are used for survival and proliferation.IL-2 is commonly used as an adjuvant in immunotherapy protocols (7). In addition to playing a critical role in survival of CD8 T cells, when presented at high levels to antigen-activated CD8 cells, IL-2 can also promote the induction of effector functions, such as granzyme B (gzmB) via STAT5 signaling, thereby functioning as a costimulatory molecule (8). However, controversy about the dual role of IL-2 in enhancing proliferation of both CD8 effector cells and CD4 regulatory T cells (Tregs), both of which express high levels of CD25, has raised some questions about the use of this cytokine in vivo (9). Recent studies have shown that the effect of the cytokine can be amplified and directed more specifically to CD8 cells rather than Tregs if IL-2 is complexed with the mAB S4B6 (10, 11). IL-15 bound to IL-15R␣, its natural ''presenting'' receptors, has been shown to have a similar effect on CD8 memory cells and tumor-infiltrated cells (12)(13)(14), and IL-7/anti-IL-7 mAb comp...

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Section: Discussionmentioning

confidence: 99%

Adjuvants targeting innate and adaptive immunity synergize to enhance tumor immunotherapy

Verdeil

Marquardt²,

Surh³

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

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“…In our studies the pA:pU motif elicited stronger anti-Tat-specific T cell responses than the pI:pC motif. The engagement of TLR-3 on antigen-presenting cells by dsRNA motifs has been shown to stimulate the secretion of cytokines that contribute to the differentiation of T cells towards the Th1 or Th2 phenotype [15]. Indeed, splenocyte cultures of mice immunized with sTat + pI:pC or pA:pU secreted IFN-c, IL-6 and IL-10.…”

Section: Discussionmentioning

confidence: 99%

“…Within the context of vaccination, certain dsRNA motifs have been shown to be highly effective in enhancing immune responses to coadministered antigens [15]. Since dsRNA motifs are negatively charged, this would favor their interaction with the basic region encompassing residues 44-61 of Tat protein.…”

Section: Introductionmentioning

confidence: 99%

The binding affinity of double‐stranded RNA motifs to HIV‐1 Tat protein affects transactivation and the neutralizing capacity of anti‐Tat antibodies elicited after intranasal immunization

et al. 2005

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In this study we examined the hypothesis that the binding affinity of two doublestranded (ds) RNA motifs to HIV-1 Tat protein might affect transactivation and the type of anti-Tat immune responses. Using surface plasmon resonance technology we demonstrated the capacity of the poly(A):poly(U) (pA:pU) motif to bind with high affinity to a totally synthetic Tat protein and to inhibit more efficiently the Tat/ transactivation response element (TAR) RNA interaction as compared to the poly(I):poly(C) (pI:pC) motif. Furthermore, the pA:pU motif was tenfold more effective in inhibiting Tat-driven transactivation than the pI:pC motif. Following intranasal immunization of mice, both dsRNA motifs enhanced the antibody (serum and mucosal) and cellular responses to Tat. However, only the serum samples of mice immunized with Tat + pI:pC inhibited Tat-driven transactivation. The profile of serum antibody subclasses together with the secreted cytokines by Tat-stimulated splenocyte cultures indicated that both dsRNA motifs favored the induction of a balanced Th1 and Th2 immune response. The demonstration in this study that two dsRNA motifs had a marked effect on Tat/TAR RNA interaction and on the neutralizing capacity of anti-Tat specific antibody responses highlights their potential for biological applications and the importance of selecting the appropriate motif as an adjuvant for vaccine design.

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“…In addition, dsRNAs induce activation and maturation of DCs. 26 Uptake of apoptotic cells transfected with recombinant SFV will thus not only provide the specific antigen but also provide the required danger signal. Induction of CTL activity upon SFV-enhE6,7 versus DNA-E7 immunization in wild-type and Tg mice.…”

mentioning

confidence: 99%

Induction of human papilloma virus E6/E7-specific cytotoxic T-lymphocyte activity in immune-tolerant, E6/E7-transgenic mice

Riezebos‐Brilman

Regts

et al. 2005

Gene Ther

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Despite promising preclinical results of various therapeutic anticancer immunization strategies, these approaches may not be effective enough to eradicate tumors in cancer patients. While most animal models are based on fastgrowing transplantable tumors, malignancies in, for example, cervical cancer patients in general develop much more slowly, which may lead to immune suppression and/or immune tolerance. As a consequence, the immunomodulating signal of any therapeutic immunization regimen should be sufficiently potent to overcome this immunocompromised condition. In previous studies, we demonstrated that an experimental vaccine against human papillomavirus (HPV)-induced cervical cancer, based on Semliki Forest virus (SFV), induces robust HPV-specific cellular immune responses in mice. Now we studied whether this strategy is potent enough to also prime a cellular immune response in immune-tolerant HPV transgenic mice, in which CTL activity cannot be induced using protein or DNA vaccines. We demonstrate that, depending on the route of immunization, SFV-expressing HPV16 E6 and E7 indeed has the capacity to induce HPV16 E7-specific cytotoxic T cells in HPVtransgenic mice. Gene Therapy (2005) Cervical cancer is the third most common cancer among women worldwide. It is caused by infection with highrisk human papillomavirus (HPV), in particular types 16, 18, 31, 33 or 45. Indeed, in over 99% of all cervical carcinomas, DNA derived from these HPV types is detectable. 1 High-risk HPVs have the capacity to transform cervical epithelial cells by integrating the open reading frames encoding the viral early proteins E6 and E7 into the host cell genome. This integration may lead to constitutive overexpression of E6 and E7, mediating transformation of the cells to a malignant phenotype. 2 Since the continued production of E6 and E7 is required for the maintenance of the transformed phenotype, E6 and E7 in fact represent tumor-specific antigens in cervical carcinoma and premalignant HPV-transformed cells. As a consequence, E6 and E7 are potential targets for immunotherapeutic intervention strategies involving induction or stimulation of cytotoxic T lymphocyte (CTL) activity against HPV-transformed cells. 3

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Noncoding RNA danger motifs bridge innate and adaptive immunity and are potent adjuvants for vaccination

Cited by 58 publications

References 25 publications

Adjuvants targeting innate and adaptive immunity synergize to enhance tumor immunotherapy

Adjuvants targeting innate and adaptive immunity synergize to enhance tumor immunotherapy

The binding affinity of double‐stranded RNA motifs to HIV‐1 Tat protein affects transactivation and the neutralizing capacity of anti‐Tat antibodies elicited after intranasal immunization

Induction of human papilloma virus E6/E7-specific cytotoxic T-lymphocyte activity in immune-tolerant, E6/E7-transgenic mice

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