The impact of sub-cellular localization and dose of tumor antigen on the efficiency cross-presentation

Abstract

Event Abstract Back to Event The impact of sub-cellular localization and dose of tumor antigen on the efficiency cross-presentation Chidozie C. Anyaegbu1, Scott A. Fisher1, Bruce Robinson1 and Richard Lake1* 1 The University of Western Australia, School of Medicine and Pharmacology, Australia One of the most effective ways the immune system uses to detect tumor antigen is through a process termed Cross-presentation. In this process, antigen presenting cells capture, process, and present exogenous tumor antigens to CD8+ T cells, a key effector population. In order to induce an effective cross-presentation mediated anti-tumor immune response, it is crucial that the immune system is able to sense low antigen concentrations, typically present in distinct sub-cellular compartments within tumor cells. This study examines the efficiency of tumor antigen cross-presentation, and addresses the hypothesis that some sub-cellular compartments are better sources of tumor antigen. We compared tumor specific T cell responses elicited by mouse B16-F10 melanoma tumors stably expressing a model antigen (CL4 epitope of haemagglutinin), in cytoplasmic, secretory, or nuclear sub-cellular compartments within the tumor-cell. All three tumor cell-lines similarly expressed approximately 3.88 x 10-9 micromoles (µmol) of CL4-antigen per cell. Our results show that cross-presentation is remarkably sensitive to antigen dose, with a threshold of inoculated antigen (0.194 µmol) being required for cross-presentation induced proliferation of adoptively transferred, Carboxyfluorescein Diacetate Succinimidyl Ester (CFSE) labelled, CL4-T cell receptor transgenic CD8+ T cells. Furthermore, nuclear localized antigen was less efficiently cross-presented, with 40% proliferation of CD8+ CL4 T cells. By contrast, its cytoplasmic and secreted counterparts induced a near maximal 80% proliferation. Notably however, gemcitabine, an apoptosis inducing chemotherapy agent, was able to double the low cross-presentation efficiency of nuclear antigens, in an antigen dose dependent manner. Taken together, our data suggests that the dose and localization of antigen within a tumor cell can influence the robustness of anti-tumor T cell responses. Moreover, gemcitabine can enhance these responses by unmasking previously ignored, potentially novel nuclear antigens, like those that tend to arise in new tumor variants to which the host’s T cell repertoire is not tolerant. These findings imply that the dose and sub-cellular localization of antigen(s) should be considered when designing chemo-immunotherapy anti-tumor strategies. Figure 1 Acknowledgements Chidozie Anyaegbu is kindly supported by the University of Western Australia Research Training Scheme (RTS) Scholarship. This work is funded by the Australian government National Health and Medical Research Council's (NHMRC), Centres of Clinical Research Excellence (CCRE) grant held by NCARD. Keywords: Subcellular localization, Tumor antigens, cross-presentation, antigen processing and presentation, Cancer Conference: 15th International Congress of Immunology (ICI), Milan, Italy, 22 Aug - 27 Aug, 2013. Presentation Type: Abstract Topic: Adaptive Immunity Citation: Anyaegbu CC, Fisher SA, Robinson B and Lake R (2013). The impact of sub-cellular localization and dose of tumor antigen on the efficiency cross-presentation. Front. Immunol. Conference Abstract: 15th International Congress of Immunology (ICI). doi: 10.3389/conf.fimmu.2013.02.00801 Copyright: The abstracts in this collection have not been subject to any Frontiers peer review or checks, and are not endorsed by Frontiers. They are made available through the Frontiers publishing platform as a service to conference organizers and presenters. The copyright in the individual abstracts is owned by the author of each abstract or his/her employer unless otherwise stated. Each abstract, as well as the collection of abstracts, are published under a Creative Commons CC-BY 4.0 (attribution) licence (https://creativecommons.org/licenses/by/4.0/) and may thus be reproduced, translated, adapted and be the subject of derivative works provided the authors and Frontiers are attributed. For Frontiers’ terms and conditions please see https://www.frontiersin.org/legal/terms-and-conditions. Received: 21 Jun 2013; Published Online: 22 Aug 2013. * Correspondence: Prof. Richard Lake, The University of Western Australia, School of Medicine and Pharmacology, Perth, Western Australia, 6009, Australia, richard.lake@uwa.edu.au Login Required This action requires you to be registered with Frontiers and logged in. To register or login click here. Abstract Info Abstract The Authors in Frontiers Chidozie C Anyaegbu Scott A Fisher Bruce Robinson Richard Lake Google Chidozie C Anyaegbu Scott A Fisher Bruce Robinson Richard Lake Google Scholar Chidozie C Anyaegbu Scott A Fisher Bruce Robinson Richard Lake PubMed Chidozie C Anyaegbu Scott A Fisher Bruce Robinson Richard Lake Related Article in Frontiers Google Scholar PubMed Abstract Close Back to top Javascript is disabled. Please enable Javascript in your browser settings in order to see all the content on this page.