Vaccine with β-Defensin 2–Transduced Leukemic Cells Activates Innate and Adaptive Immunity to Elicit Potent Antileukemia Responses

Ma, Xiaotong; Xu, Bin; An, Lili; Dong, Chen; Lin, Yuan; Yang, Shan; Wu, Ke‐Fu

doi:10.1158/0008-5472.can-05-2891

Cited by 31 publications

(33 citation statements)

References 44 publications

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“…Several alarmins have been reported to have the capacity to enhance antitumor immunity. Mouse b-defensin 2 can promote the generation of antitumor immunity against leukemia and melanoma through activation of DCs, T cell, and NK cells (12,29,34). HSPs are also reported to be capable of promoting antitumor CD8 responses (35,36).…”

Section: Discussionmentioning

confidence: 99%

The Alarmin HMGN1 Contributes to Antitumor Immunity and Is a Potent Immunoadjuvant

et al. 2014

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Alarmins are endogenous mediators that are elicited rapidly in response to danger signals, enhancing innate and adaptive immune responses by promoting the recruitment and maturation of antigen-presenting cells (APC). The nucleosome-binding protein HMGN1 is a potent alarmin that binds TLR4 and induces antigen-specific Th1 immune responses, but its contributions to antitumor immunity have not been explored. We found that ovalbumin (OVA)-expressing EG7 mouse thymoma cells grew much faster in Hmgn1-deficient mice than littermate-matched controls. Tumor-bearing Hmgn1 À/À mice generated fewer OVA-specific CD8 cells in the spleen than EG7-bearing Hmgn1 þ/þ mice, suggesting that HMGN1 supported T cell-mediated antitumor immunity. In addition, EG7 tumors expressing HMGN1 grew more slowly than control EG7 tumors, suggesting greater resistance to HMGN1-expressing tumors. This resistance relied on T cell-mediated immunity because it was abolished by in vivo depletion of CD4 þ and CD8 þ T cells. Moreover, mice vaccinated with a DNA vector expressing an HMGN1-gp100 fusion protein manifested gp100-specific, Th1-polarized immune responses, acquiring resistance to challenge with mouse B16F1 melanoma. Overall, our findings show that HMGN1 contributes to antitumor immunity and it may offer an effective adjuvant to heighten responses to cancer vaccines. Cancer Res; 74(21); 5989-98. Ó2014 AACR.

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Section: Discussionmentioning

confidence: 99%

The Alarmin HMGN1 Contributes to Antitumor Immunity and Is a Potent Immunoadjuvant

et al. 2014

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“…In addition, we also found that inoculation of mice with L1210-MBD2 induced augmented interleukin-12 (IL-12) and interferon-g (IFN-g) production. 3 These findings suggest that MBD2 acts as a critical link between the innate immune system and the adaptive immune response.…”

Section: Introductionmentioning

confidence: 91%

Synergistic antileukemia effect of combinational gene therapy using murine b-defensin 2 and IL-18 in L1210 murine leukemia model

Zhang

et al. 2007

Gene Ther

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Murine b-defensin 2 (MBD2) is not only chemotactic for immature dendritic cells but also activates them by Toll-like receptor 4. We have previously demonstrated that vaccine with MBD2 elicited potent antileukemia responses in the L1210 murine model. Interleukin-18 (IL-18) is an essential cytokine for the generation of Th1 response and natural killer cells and cytotoxic T lymphocytes (CTL) activation. As MBD2 and IL-18 appear to function on different components required by an effective antitumor immune response including both innate and adaptive immunity, we investigated whether combinatorial delivery of MBD2 and IL-18 transduced L1210 cells could elicit synergistic antileukemia effects. First, we constructed a single plasmid vector carrying both pro-IL-18 and IL-1b converting enzyme (ICE) genes, and found that transfection of this vector into L1210 cells resulted in efficient secretion of bioactive IL-18. Combinatorial delivery of MBD2 and pro-IL-18-ICE modified L1210 cells conferred a superior inhibition of leukemogenicity over either L1210-MBD2 or L1210-pro-IL-18-ICE alone; moreover, the survived mice developed long-lasting protective immunity as determined by rechallenge experiments. This combined vaccine also elicited the most marked therapeutic effect, CTL activity and interferon-g production. These results suggest that the combination of MBD2 and IL-18 induces more effective antileukemia activity and provides a promising strategy for cancer therapy.

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“…They modulate the cytokine response of mononuclear blood cells [11], and promote systemic antigen-or tumor-specific immune responses [12][13][14][15]. In keeping with these findings, human b-defensin (HBD)-1 to -3 as well as murine b-defensin (mBD)-2, -3 and -29 were shown to selectively chemoattract memory T lymphocytes and/or immature DC via CCR6 [12, [16][17][18].…”

Section: Introductionmentioning

confidence: 99%

β‐Defensins chemoattract macrophages and mast cells but not lymphocytes and dendritic cells: CCR6 is not involved

et al. 2007

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b-Defensins are natural peptide antibiotics whose immunomodulatory functions are poorly understood. In the present study, macrophages were found to migrate to human b-defensins (HBD)-1 to -4 using Ga i proteins as well as MAPK ERK, p38 and JNK as signal transducers. In addition, mast cells responded to HBD-1 to -4 with calcium fluxes as well as chemotaxis, which increased upon stimulation with IgE plus antigen or ionomycin. In contrast, human b-defensins were unable to induce migration of memory lymphocytes and dendritic cells (DC). Similar to HBD, the murine b-defensin (mBD)-8 mobilized macrophages and lacked the ability to recruit memory T cells. These findings were unexpected as CCR6 on memory T cells and DC has been previously observed to be a receptor for human b-defensins. In support of our findings, however, RBL-2H3 as well as 300.19 cells stably expressing CCR6 proved to be unresponsive to HBD-2 and -3. Intriguingly, our observation of a PKC-independent homologous desensitization between HBD-1 to -4 suggests a common receptor for HBD. In summary, chemoattraction of macrophages and mast cells is evolutionary conserved within the b-defensin family despite a considerable sequence variation and distinct antimicrobial activities. However, CCR6 is not a functional receptor for b-defensins.

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Vaccine with β-Defensin 2–Transduced Leukemic Cells Activates Innate and Adaptive Immunity to Elicit Potent Antileukemia Responses

Cited by 31 publications

References 44 publications

The Alarmin HMGN1 Contributes to Antitumor Immunity and Is a Potent Immunoadjuvant

The Alarmin HMGN1 Contributes to Antitumor Immunity and Is a Potent Immunoadjuvant

Synergistic antileukemia effect of combinational gene therapy using murine b-defensin 2 and IL-18 in L1210 murine leukemia model

β‐Defensins chemoattract macrophages and mast cells but not lymphocytes and dendritic cells: CCR6 is not involved

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