Development of New Photo-Activated Local Cancer Immunotherapy: Targeting Tumor Infiltrating Regulatory T Cells

CD4+CD25+Foxp3+ regulatory T cells (Tregs) are known to suppress immune responses. Treg-mediated immunosuppression is a key mechanism for tumor immune-evasion, which could lead cancer immunotherapies to failures. Systemic depletion of Tregs has been tried by using antibodies against them; however, intravenously delivering these antibodies might not sufficiently deplete Tregs in tumor microenvironment or could deplete effector cells. Furthermore, systemic severe autoimmune responses could cause potential side effects. To address these problems, we exploited near infrared photoimmunotherapy (NIR-PIT) to deplete only intratumoral Tregs with anti-CD25-antibody aiming to induce anti-tumor immune activation within manageable side effects. NIR-PIT is a recently developed cancer treatment that combines the specificity of intravenously injected antibodies that target tumors/cells with the toxicity induced by photosensitizers activated by NIR-light. Depletion of intratumoral-Tregs with a local CD25-target-NIR-PIT rapidly induced CD8 T- and NK-cell activation, thereby restoring local anti-tumor immunity. Consequently, activated immunity led to regression of not only NIR-PIT-treated-tumors but also non-NIR-light-exposed-tumors in separate parts of the body (Abscopal Effect). These anti-tumor effects were partially CD8, NK, or INFg-dependent. Taken together, Local CD25-target-NIR-PIT depleted intratumoral T-regs, which modulated tumor-microenvironment to rapid rejection of tumors, and could activate other immune cells. Local CD25-target-NIR-PIT also induced antitumor-effect on distant non-irradiated tumor by rapid activation and cytotoxic action of CD8 T cells and NK cells. These observations suggest that local CD25-target-NIR-PIT may be a promising new strategy for cancer immunotherapy. This study suggests a promising new strategy for cancer immunotherapy.