Frequent adaptive immune responses against arginase-1. (4th March 2018)

• Record Type: Journal Article
• Authors: Martinenaite, Evelina; Mortensen, Rasmus Erik Johansson; Hansen, Morten; Orebo Holmström, Morten; Munir Ahmad, Shamaila; Grønne Dahlager Jørgensen, Nicolai; Met, Özcan; Donia, Marco; Svane, Inge Marie; Andersen, Mads Hald
• Is Part Of: Oncoimmunology. Volume 7:Number 3(2018)
• Publication Date: 2018-03-04
• Subjects: arginase -- antigens -- Inflammation and cancer -- Immunomodulation -- MDSC -- Models of anticancer vaccination -- Models of immunostimulation -- peptide vaccine -- T cells; Tumors -- Immunological aspects -- Periodicals; Neoplasms -- therapy -- Periodicals; Immunotherapy -- Periodicals; 616.994
• DOI: 10.1080/2162402X.2017.1404215
• Languages: English
• ISSNs: 2162-402X

Abstract

ABSTRACT: The enzyme arginase-1 reduces the availability of arginine to tumor-infiltrating immune cells, thus reducing T-cell functionality in the tumor milieu. Arginase-1 is expressed by some cancer cells and by immune inhibitory cells, such as myeloid-derived suppressor cells (MDSCs) and tumor-associated macrophages (TAMs), and its expression is associated with poor prognosis. In the present study, we divided the arginase-1 protein sequence into overlapping 20-amino-acid-long peptides, generating a library of 31 peptides covering the whole arginase-1 sequence. Reactivity towards this peptide library was examined in PBMCs from cancer patients and healthy individuals. IFNγ ELISPOT revealed frequent immune responses against multiple arginase-1-derived peptides. We further identified a hot-spot region within the arginase-1 protein sequence containing multiple epitopes recognized by T cells. Next, we examined in vitro-expanded tumor-infiltrating lymphocytes (TILs) isolated from melanoma patients, and detected arginase-1-specific T cells that reacted against epitopes from the hot-spot region. Arginase-1-specific CD4+T cells could be isolated and expanded from peripheral T cell pool of a patient with melanoma, and further demonstrated the specificity and reactivity of these T cells. Overall, we showed that arginase-1-specific T cells were capable of recognizing arginase-1-expressing cells. The activation of arginase-1-specific T cells by vaccination is an attractive approach to target arginase-1-expressing malignant cells and inhibitory immune cells. In the clinical setting, the induction of arginase-1-specific immune responses could induce or increase Th1 inflammation at the sites of tumors that are otherwise excluded due to infiltration with MDSCs and TAMs.