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

Author

Alexander A. Perakis, The University of Texas MD Anderson Cancer Center UTHealth Graduate School of Biomedical SciencesFollow

Author ORCID Identifier

https://orcid.org/0000-0002-8172-7281

Date of Graduation

5-2019

Document Type

Dissertation (PhD)

Program Affiliation

Immunology

Degree Name

Doctor of Philosophy (PhD)

Advisor/Committee Chair

Gheath Al-Atrash, D.O., Ph.D.

Committee Member

Jeffrey J. Molldrem, M.D.

Committee Member

Michelle C. Barton, Ph.D.

Committee Member

Michael A. Curran, Ph.D.

Committee Member

Gregory A. Lizee, Ph.D.

Committee Member

Stephanie S. Watowich, Ph.D.

Abstract

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 in vitroand in vivo. 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.

Keywords

multiple myeloma, immunotherapy, cross-presentation, antibody