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Route of antigen delivery impacts the immunostimulatory activity of dendritic cell-based vaccines for hepatocellular carcinoma

Pardee, AD and Yano, H and Weinstein, AM and Ponce, AAK and Ethridge, AD and Normolle, DP and Vujanovic, L and Mizejewski, GJ and Watkins, SC and Butterfield, LH (2015) Route of antigen delivery impacts the immunostimulatory activity of dendritic cell-based vaccines for hepatocellular carcinoma. Journal for ImmunoTherapy of Cancer, 3 (1).

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Background: Dendritic cells (DC) are uniquely equipped to capture, process, and present antigens from their environment. The context in which an antigen is acquired by DC helps to dictate the subsequent immune response. Cancer vaccination promotes antitumor immunity by directing an immune response to antigens expressed by tumors. We have tested the tumor-associated antigen alpha-fetoprotein (AFP) as an immunotherapy target. The majority of hepatocellular carcinomas (HCC) upregulate and secrete this oncofetal antigen. Methods: To develop cancer vaccines for HCC capable of promoting potent tumor-specific T cell responses, we tested adenovirally-encoded synthetic AFP, with or without its signal sequence, as well as protein forms of AFP and compared intracellular routing and subsequent antigen-specific CD8+ and CD4+ T cell responses. Results: Surprisingly, the secreted form of antigen was superior for both CD4+ and CD8+ T cell activation. We also examined the mechanism through which AFP protein is endocytosed and trafficked in human DC. We identify the mannose receptor (MR/CD206) as the primary uptake pathway for both normal cord blood-derived AFP (nAFP) and tumor-derived AFP (tAFP) proteins. While in healthy donors, nAFP and tAFP were cross-presented to CD8+ T cells similarly and CD4+ T cell responses were dependent upon MR-mediated uptake. In HCC patient cells, tAFP was more immunogenic, and CD4+ T cell responses were not MR-dependent. Conclusions: Secreted, cytoplasmically retained, and endocytosed forms of AFP utilize unique uptake and processing pathways, resulting in different immunologic responses from the induced antigen-specific CD4+ and CD8+ T cells and between healthy donors and HCC patients. Collectively, these data elucidate pathways of spontaneous and induced anti-tumor immunity in HCC patients to this secreted antigen.


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Item Type: Article
Status: Published
CreatorsEmailPitt UsernameORCID
Pardee, AD
Yano, Hhiy12@pitt.eduHIY12
Weinstein, AM
Ponce, AAK
Ethridge, AD
Normolle, DPdpn7@pitt.eduDPN70000-0001-8675-5014
Vujanovic, Llnvst3@pitt.eduLNVST3
Mizejewski, GJ
Watkins, SCsimon.watkins@pitt.eduSWATKINS
Butterfield, LHlhb3@pitt.eduLHB3
Centers: Other Centers, Institutes, Offices, or Units > Pittsburgh Cancer Institute
Date: 21 July 2015
Date Type: Publication
Journal or Publication Title: Journal for ImmunoTherapy of Cancer
Volume: 3
Number: 1
DOI or Unique Handle: 10.1186/s40425-015-0077-x
Schools and Programs: School of Public Health > Biostatistics
School of Medicine > Cell Biology
School of Medicine > Dermatology
School of Medicine > Immunology
School of Medicine > Medicine
School of Medicine > Surgery
Refereed: Yes
Date Deposited: 10 Aug 2016 17:27
Last Modified: 04 Jan 2023 11:56


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