Lecog et al. identified two MHCI-binding peptides derived from CCL22, a macrophage-derived immunosuppressive chemokine that recruits CCR4+ Tregs. Peptide vaccination s.c. of mice bearing s.c. or orthotopic syngeneic CCL22+ tumors induced IFNγ secretion by ex vivo peptide-restimulated spleen and LN cells and delayed tumor growth, decreased metastatic burden and prolonged host survival. In the TME, vaccination increased PD1+CD8+ T cells and pDCs, decreased Tregs and M2 macrophages (a primary CCL22 source), upregulated immune response genes and downregulated genes associated with tumor progression.
Contributed by Paula Hochman
ABSTRACT: CCL22 is a macrophage-derived immunosuppressive chemokine that recruits regulatory T cells through the CCL22:CCR4 axis. CCL22 was shown to play a key role in suppressing anti-cancer immune responses in different cancer types. Recently, we showed that CCL22-specific T cells generated from cancer patients could kill CCL22-expressing tumor cells and directly influence the levels of CCL22 in vitro. The present study aimed to provide a rationale for developing a CCL22-targeting immunotherapy. Vaccination with CCL22-derived peptides induced CCL22-specific T-cell responses in both BALB/c and C57BL/6 mice, assessed by interferon-γ secretion ex vivo. Anti-tumor efficacy of the peptides was evaluated in mouse models engrafted with syngeneic tumor models showing a reduced tumor growth and prolonged survival of the treated mice. Vaccination induced changes in the cellular composition of immune cells that infiltrated the tumor microenvironment assessed with multicolor flow cytometry. In particular, the infiltration of CD8+ cells and M1 macrophages increased, which increased the CD8/Treg and the M1/M2 macrophage ratio. This study provided preclinical evidence that targeting CCL22 with CCL22 peptide vaccines modulated the immune milieu in the tumor microenvironment. This modulation led to an augmentation of anti-tumor responses. This study provided a rationale for developing a novel immunotherapeutic modality in cancer.
Author Info: (1) Department of Research and Development, IO Biotech ApS, Copenhagen, Denmark. National Center for Cancer Immune Therapy (CCIT-DK), Department of Oncology, Copenhagen University
Author Info: (1) Department of Research and Development, IO Biotech ApS, Copenhagen, Denmark. National Center for Cancer Immune Therapy (CCIT-DK), Department of Oncology, Copenhagen University Hospital, Herlev, Denmark. (2) Department of Research and Development, IO Biotech ApS, Copenhagen, Denmark. (3) Department of Research and Development, IO Biotech ApS, Copenhagen, Denmark. (4) Section for Bioinformatics, Department of Health Technology, Technical University of Denmark, Kongens Lyngby, Denmark. (5) Department of Research and Development, IO Biotech ApS, Copenhagen, Denmark. National Center for Cancer Immune Therapy (CCIT-DK), Department of Oncology, Copenhagen University Hospital, Herlev, Denmark. (6) National Center for Cancer Immune Therapy (CCIT-DK), Department of Oncology, Copenhagen University Hospital, Herlev, Denmark. (7) Section for Bioinformatics, Department of Health Technology, Technical University of Denmark, Kongens Lyngby, Denmark. (8) Department of Research and Development, IO Biotech ApS, Copenhagen, Denmark. (9) Department of Research and Development, IO Biotech ApS, Copenhagen, Denmark. (10) National Center for Cancer Immune Therapy (CCIT-DK), Department of Oncology, Copenhagen University Hospital, Herlev, Denmark. Department of Immunology and Microbiology, University of Copenhagen, Copenhagen, Denmark.
