BackgroundCancer progression is associated with an increased immune suppression at the tumor site. Arginase-1 is an enzyme well-known for its involvement in metabolic immune regulation. At the tumor site, arginase-1 acts by reducing availability of L-arginine to the infiltrating immune cells thus reducing T cell functionality and proliferation. While arginase-1 is expressed by some tumor cells, it has also been shown to be produced by immune inhibitory myeloid cells, such as myeloid derived suppressor cells (MDSCs), tumor associated macrophages (TAMs) and is associated with poor prognosis. Previously, we demonstrated that spontaneous CD4+ and CD8+ T-cell immune responses against arginase-derived, HLA-restricted peptides can be found in both cancer patients and healthy individuals (Martinenaite et al, 2018, DOI: 10.1080/2162402X.2017.1404215). These T cells are present in the memory T cell compartment, and that they are activated in arginase-1 inducing conditions, such as presence of TH2 cytokines IL-4 or IL-13 in vitro (Martinenaite et al, 2019, DOI: 10.1038/s41423-019-0231-3 and DOI: 10.1007/s00262-019-02425-6).Methods and ResultsIn order to explore if arginase-1-specific T cells have a potential role in modulation of immune homeostasis, human arginase-1-specific memory T cells were isolated and expanded for functional characterization. We show that arginase-1-specific T cells specifically recognize arginase-1 expressing cells, such as mRNA transfected autologous dendritic cells (DCs) and B cells as well as M2 polarized macrophages in vitro. In addition, activated arginase-1-specific T cells produce pro-inflammatory cytokines IFNγ and TNFα. Secretion of TH1 cytokines by these T cells suggests potential role as potent immune modulators in the tumor microenvironment, since many arginase-1 expressing myeloid cells are not terminally differentiated and they can be re-polarized to an immunostimulatory, M1-like phenotype. We also observed that targeting of M2-polarized arginase-1 expressing monocytic leukemia cell line THP-1 with arginase-1-specific CD4+ T cells induces upregulation of PD-L1 on the THP-1 cells. Furthermore, we demonstrate that an arginase-1-derive peptide vaccine has a therapeutic effect in syngeneic mouse tumor models (B16 and MC38), both as monotherapy and in combination with anti-PD-1 treatment. The therapeutic effect was associated with increased immune infiltration in the peptide vaccinated mice compared to the control.ConclusionsOur study provides evidence that immune modulatory vaccination targeting arginase-1 is an intriguing way of targeting the immune suppressive microenvironment.Disclosure InformationE. Martinenaite: A. Employment (full or part-time); Significant; IO Biotech. M. Aaboe Joergensen: None. R.E. Johansson Mortensen: None. S. Munir Ahmad: None. S.E. Weis-Banke: None. M. Orebo Holmström: None. A. Wakatsuki Pedersen: A. Employment (full or part-time); Significant; IO Biotech. Ö. Met: None. I.M. Svane: F. Consultant/Advisory Board; Significant; IO Biotech. M. Hald Andersen: A. Employment (full or part-time); Significant; IO Biotech.
A TLR4 agonist improves immune checkpoint blockade treatment by increasing the ratio of effector to regulatory cells within the tumor microenvironment