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Oncoimmunology. 2017 Dec 26;7(3):e1404215. doi: 10.1080/2162402X.2017.1404215. eCollection 2018.

Frequent adaptive immune responses against arginase-1.

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Center for Cancer Immune Therapy (CCIT), Department of Hematology, Copenhagen University Hospital, Herlev, Denmark.
Department of Hematology, Zealand University Hospital, Roskilde, Denmark.
Department of Oncology, Copenhagen University Hospital Herlev, Herlev, Denmark.
Department of Immunology and Microbiology, University of Copenhagen, Copenhagen, Denmark.


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.


Immunomodulation; Inflammation and cancer; MDSC; Models of anticancer vaccination; Models of immunostimulation; T cells; antigens; arginase; peptide vaccine

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