Combined immunotherapy: CTLA-4 blockade potentiates anti-tumor response induced by transcutaneous immunization. Issue 3 (September 2017)

• Record Type: Journal Article
• Authors: Rausch, Johanna; Lopez, Pamela Aranda; Bialojan, Ariane; Denny, Mark; Langguth, Peter; Probst, Hans Christian; Schild, Hansjörg; Radsak, Markus P.
• Is Part Of: Journal of dermatological science. Volume 87:Issue 3(2017:Sep.)
• Page Start: 300
• Page End: 306
• Publication Date: 2017-09
• Subjects: TCI transcutaneous immunization -- CTL cytotoxic T-cell -- TLR7 toll-like receptor 7 -- CTLA-4 cytotoxic T-lymphocyte associated antigen 4 -- s.c subcutaneous -- i.p. intraperitoneal -- Treg regulatory T-cell -- IFN interferon -- IL interleukin -- APC antigen presenting cell; CTLA-4 antibody -- Transcutaneous immunization -- Cytotoxic T cells -- B16 OVA melanoma -- TLR-7 -- Imiquimod; Dermatology -- Periodicals; Skin Diseases -- Periodicals; Dermatologie -- Périodiques; 616.5005
• DOI: 10.1016/j.jdermsci.2017.06.013
• Languages: English
• ISSNs: 0923-1811

Abstract

Highlights: Check point blockade of CTLA-4 augments TCI mediated T-cell responses and supports memory formation. Combined immunotherapy with TCI and CTLA-4 blockade improves survival of mice with B16 OVA melanoma. In TCI, enhanced T-cell responses by CTLA-4 blockade are mainly independent of Treg cells. Abstract: Background: The epidermal application of the Toll Like Receptor 7 agonist imiquimod and a T-cell peptide epitope (transcutaneous immunization, TCI) mediates systemic peptide-specific cytotoxic T-cell (CTL) responses and leads to tumor protection in a prophylactic tumor setting. However, it does not accomplish memory formation or permanent defiance of tumors in a therapeutic set-up. As a distinct immunologic approach, CTLA-4 blockade augments systemic immune responses and has shown long-lasting effects in preclinical experiments as well as in clinical trials. Objective: The study investigates the vaccination capacity of TCI in combination with the checkpoint inhibitor CTLA-4 in matters of primary response, memory formation and tumor protection and characterizes the role of regulatory T cells (Tregs). Methods: After performing TCI with IMI-Sol (containing 5% Imiquimod) and the model epitope SIINFEKL, 6–8 week old C57BL/6 mice received anti-CTLA-4 antibody either s.c or i.p. The CTL responses and frequency of peptide specific CD8 + T-cells were then evaluated on day 8. To determine anti-tumor effects, a therapeutic tumor challenge with B16 OVA melanoma was performed. Results: The combination of s.c. anti-CTLA-4 antibody and TCI leads to an enhanced systemic cytotoxic response, to memory formation and allows significantly improved survival in a tumor setting with B16 OVA melanoma. Towards the mechanism, we show that in this vaccination protocol the CTLA-4 antibody acts mainly Treg-independent. Conclusion: We demonstrate that the combination of TCI with IMI-Sol and anti-CTLA-4 can confer potent immune responses and tumor-protection. These results might contribute to the development of advanced vaccination approaches targeting tumors or persistent infectious diseases.