TY - JOUR

T1 - The metabolic enzyme arginase-2 is a potential target for novel immune modulatory vaccines

AU - Weis-Banke, Stine Emilie

AU - Hübbe, Mie Linder

AU - Holmström, Morten Orebo

AU - Jørgensen, Mia Aaboe

AU - Bendtsen, Simone Kloch

AU - Martinenaite, Evelina

AU - Carretta, Marco

AU - Svane, Inge Marie

AU - Ødum, Niels

AU - Pedersen, Ayako Wakatsuki

AU - Met, Özcan

AU - Madsen, Daniel Hargbøl

AU - Andersen, Mads Hald

PY - 2020

Y1 - 2020

N2 - One way that tumors evade immune destruction is through tumor and stromal cell expression of arginine-degrading enzyme arginase-2 (ARG2). Here we describe the existence of pro-inflammatory effector T-cells that recognize ARG2 and can directly target tumor and tumor-infiltrating cells. Using a library of 34 peptides covering the entire ARG2 sequence, we examined reactivity toward these peptides in peripheral blood mononuclear cells from cancer patients and healthy individuals. Interferon-γ ELISPOT revealed frequent immune responses against several of the peptides, indicating that ARG2–specific self-reactive T-cells are natural components of the human T-cell repertoire. Based on this, the most immunogenic ARG2 protein region was further characterized. By identifying conditions in the microenvironment that induce ARG2 expression in myeloid cells, we showed that ARG2-specific CD4T-cells isolated and expanded from a peripheral pool from a prostate cancer patient could recognize target cells in an ARG2-dependent manner. In the ‘cold’ in vivo tumor model Lewis lung carcinoma, we found that activation of ARG2-specific T-cells by vaccination significantly inhibited tumor growth. Immune-modulatory vaccines targeting ARG2 thus are a candidate strategy for cancer immunotherapy.

AB - One way that tumors evade immune destruction is through tumor and stromal cell expression of arginine-degrading enzyme arginase-2 (ARG2). Here we describe the existence of pro-inflammatory effector T-cells that recognize ARG2 and can directly target tumor and tumor-infiltrating cells. Using a library of 34 peptides covering the entire ARG2 sequence, we examined reactivity toward these peptides in peripheral blood mononuclear cells from cancer patients and healthy individuals. Interferon-γ ELISPOT revealed frequent immune responses against several of the peptides, indicating that ARG2–specific self-reactive T-cells are natural components of the human T-cell repertoire. Based on this, the most immunogenic ARG2 protein region was further characterized. By identifying conditions in the microenvironment that induce ARG2 expression in myeloid cells, we showed that ARG2-specific CD4T-cells isolated and expanded from a peripheral pool from a prostate cancer patient could recognize target cells in an ARG2-dependent manner. In the ‘cold’ in vivo tumor model Lewis lung carcinoma, we found that activation of ARG2-specific T-cells by vaccination significantly inhibited tumor growth. Immune-modulatory vaccines targeting ARG2 thus are a candidate strategy for cancer immunotherapy.

KW - Anti-Tregs

KW - ARG2

KW - immune modulation

KW - T-win

U2 - 10.1080/2162402X.2020.1771142

DO - 10.1080/2162402X.2020.1771142

M3 - Journal article

C2 - 32923127

AN - SCOPUS:85086110849

VL - 9

JO - OncoImmunology

JF - OncoImmunology

SN - 2162-4011

IS - 1

M1 - 1771142

ER -