Cross-Presentation Is A Source of Tumor Antigens For Multiple Myeloma Immunotherapy

<p>Cross-presentation is an essential bridge between the innate and adaptive arms of the immune system where antigen presenting cells (APCs) prime cytotoxic T cell responses. We have recently identified cross-presentation as a mechanism by which solid tumors present exogenous antigens. We therefore hypothesized that multiple myeloma would be capable of cross-presentation as these cells are derived from B cells, known APCs. We explored the capacity of multiple myeloma to cross-present PR1, a human leukocyte antigen (HLA)-A2 nonameric peptide that is derived from neutrophil elastase (NE) and proteinase 3 (P3), and the ability to treat multiple myeloma using PR1-targeting immunotherapies. Here we demonstrate that multiple myeloma cells lack endogenous NE and P3 expression, possess the ability to take up exogenous NE and P3 and cross-present PR1. This process employs the cytosolic antigen presentation machinery including the proteasome, Golgi, and TAP. Subsequent PR1 cross-presentation renders multiple myeloma cells susceptible to PR1-CTL and anti-PR1/HLA-A2 antibody, both <em>in vitro</em>and <em>in vivo</em>. To our knowledge, this is the first report of multiple myeloma cross-presenting tumor antigens. Collectively, our data demonstrate that PR1 is a novel tumor antigen in multiple myeloma and can be effectively targeted using PR1-targeting immunotherapies. Our study suggests that the multiple myeloma antigen repertoire is much larger than previously appreciated, and that there is a new catalogue of potential immunotherapeutic targets in multiple myeloma that can be derived from exogenous antigens.</p>

Name thesis:degree_name

Doctor of Philosophy (PhD)

Level thesis:degree_level

Dissertation (PhD)

Year dc:date.available

2019

Authors dc:creator

• Perakis, Alexander A.
• <p>https://orcid.org/0000-0002-8172-7281</p>

Contributors dc:contributor

• Gheath Al-Atrash, D.O., Ph.D.
• Jeffrey J. Molldrem, M.D.
• Michelle C. Barton, Ph.D.

• multiple myeloma
• immunotherapy
• cross-presentation
• antibody
• Biology
• Cancer Biology
• Immunology and Infectious Disease
• Medicine and Health Sciences

Repository record dc:identifier

https://digitalcommons.library.tmc.edu/utgsbs_dissertations/949

OAI identifier oai:identifier

oai:digitalcommons.library.tmc.edu:utgsbs_dissertations-1994