Frequent adaptive immune responses against arginase-1
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Frequent adaptive immune responses against arginase-1. / 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.
I: OncoImmunology, Bind 7, Nr. 3, e1404215, 2018.Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › fagfællebedømt
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TY - JOUR
T1 - Frequent adaptive immune responses against arginase-1
AU - Martinenaite, Evelina
AU - Mortensen, Rasmus Erik Johansson
AU - Hansen, Morten
AU - Orebo Holmström, Morten
AU - Munir Ahmad, Shamaila
AU - Grønne Dahlager Jørgensen, Nicolai
AU - Met, Özcan
AU - Donia, Marco
AU - Svane, Inge Marie
AU - Andersen, Mads Hald
PY - 2018
Y1 - 2018
N2 - 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.
AB - 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.
KW - antigens
KW - arginase
KW - Immunomodulation
KW - Inflammation and cancer
KW - MDSC
KW - Models of anticancer vaccination
KW - Models of immunostimulation
KW - peptide vaccine
KW - T cells
U2 - 10.1080/2162402X.2017.1404215
DO - 10.1080/2162402X.2017.1404215
M3 - Journal article
C2 - 29399404
AN - SCOPUS:85039038543
VL - 7
JO - OncoImmunology
JF - OncoImmunology
SN - 2162-4011
IS - 3
M1 - e1404215
ER -
ID: 188361331