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.