title: CCL22-specific T Cells: Modulating the immunosuppressive tumor microenvironment.
abstract: Tumor cells and tumor-infiltrating macrophages produce the chemokine CCL22, which attracts regulatory T cells (Tregs) into the tumor microenvironment, decreasing anticancer immunity. Here, we investigated the possibility of targeting CCL22-expressing cells by activating specific T cells. We analyzed the CCL22 protein signal sequence, identifying a human leukocyte antigen A2- (HLA-A2-) restricted peptide epitope, which we then used to stimulate peripheral blood mononuclear cells (PMBCs) to expand populations of CCL22-specific T cellsin vitro. T cells recognizing an epitope derived from the signal-peptide of CCL22 will recognize CCL22-expressing cells even though CCL22 is secreted out of the cell. CCL22-specific T cells recognized and killed CCL22-expressing cancer cells. Furthermore, CCL22-specific T cells lysed acute monocytic leukemia cells in a CCL22 expression-dependent manner. Using the Enzyme-Linked ImmunoSPOT assay, we examined peripheral blood mononuclear cells from HLA-A2+ cancer patients and healthy volunteers for reactivity against the CCL22-derived T-cell epitope. This revealed spontaneous T-cell responses against the CCL22-derived epitope in cancer patients and in healthy donors. Finally, we performed tetramer enrichment/depletion experiments to examine the impact of HLA-A2-restricted CCL22-specific T cells on CCL22 levels among PMBCs. The addition or activation of CCL22-specific T cells decreased the CCL22 level in the microenvironment. Activating CCL22-specific T cells (e.g., by vaccination) may directly target cancer cells and tumor-associated macrophages, thereby modulating Treg recruitment into the tumor environment and augmenting anticancer immunity.
authors.affiliation: Center for Cancer Immune Therapy (CCIT), Department of Hematology, Copenhagen University Hospital , Herlev, Denmark.
authors.forename: Evelina
authors.initials: E
authors.lastname: Martinenaite
authors.affiliation: Center for Cancer Immune Therapy (CCIT), Department of Hematology, Copenhagen University Hospital , Herlev, Denmark.
authors.forename: Shamaila
authors.initials: S
authors.lastname: Munir Ahmad
authors.affiliation: Center for Cancer Immune Therapy (CCIT), Department of Hematology, Copenhagen University Hospital , Herlev, Denmark.
authors.forename: Morten
authors.initials: M
authors.lastname: Hansen
authors.affiliation: Center for Cancer Immune Therapy (CCIT), Department of Hematology, Copenhagen University Hospital, Herlev, Denmark; Department of Oncology, Copenhagen University Hospital, Herlev, Denmark.
authors.forename: Özcan
authors.initials: Ö
authors.lastname: Met
authors.affiliation: Center for Cancer Immune Therapy (CCIT), Department of Hematology, Copenhagen University Hospital , Herlev, Denmark.
authors.forename: Marie Wulff
authors.initials: MW
authors.lastname: Westergaard
authors.affiliation: Center for Cancer Immune Therapy (CCIT), Department of Hematology, Copenhagen University Hospital , Herlev, Denmark.
authors.forename: Stine Kiaer
authors.initials: SK
authors.lastname: Larsen
authors.affiliation: Center for Cancer Immune Therapy (CCIT), Department of Hematology, Copenhagen University Hospital , Herlev, Denmark.
authors.forename: Tobias Wirenfeldt
authors.initials: TW
authors.lastname: Klausen
authors.affiliation: Center for Cancer Immune Therapy (CCIT), Department of Hematology, Copenhagen University Hospital, Herlev, Denmark; Department of Oncology, Copenhagen University Hospital, Herlev, Denmark.
authors.forename: Marco
authors.initials: M
authors.lastname: Donia
authors.affiliation: Center for Cancer Immune Therapy (CCIT), Department of Hematology, Copenhagen University Hospital, Herlev, Denmark; Department of Oncology, Copenhagen University Hospital, Herlev, Denmark.
authors.forename: Inge Marie
authors.initials: IM
authors.lastname: Svane
authors.affiliation: Center for Cancer Immune Therapy (CCIT), Department of Hematology, Copenhagen University Hospital, Herlev, Denmark; Department of Immunology and Microbiology, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Mads Hald
authors.initials: MH
authors.lastname: Andersen
keywords: Antigen; CCL22; T cells; Tregs; anti-Tregs