Low-dose total body irradiation facilitates antitumoral Th1 immune responses
| Autor: | Manfred Kneilling, Dominik Sonanini, Philipp Knopf, Barbara F. Schörg, Christoph M. Griessinger, Klaus Dittmann, Martin Röcken, Bernd J. Pichler |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
medicine.drug_class
T cell medicine.medical_treatment Medicine (miscellaneous) Monoclonal antibody cancer immunology Immunotherapy Adoptive B7-H1 Antigen Cell therapy T helper cells combined immunotherapy Mice Immune system Antigens CD Antigens Neoplasm Total body irradiation Positron Emission Tomography Computed Tomography medicine Animals Tissue Distribution Pharmacology Toxicology and Pharmaceutics (miscellaneous) Cancer immunology Mice Inbred C3H RIP1-Tag2 business.industry Optical Imaging Immunity Antibodies Monoclonal Immunotherapy Th1 Cells Lymphocyte Activation Gene 3 Protein Immune checkpoint Pancreatic Neoplasms medicine.anatomical_structure Cancer research Female business Whole-Body Irradiation Research Paper |
| Zdroj: | Theranostics |
| ISSN: | 1838-7640 |
| Popis: | CD4+ T helper cells are capable of mediating long-term antitumoral immune responses. We developed a combined immunotherapy (COMBO) using tumor antigen-specific T helper 1 cells (Tag-Th1), dual PD-L1/LAG-3 immune checkpoint blockade, and a low-dose total body irradiation (TBI) of 2 Gy, that was highly efficient in controlling the tumor burden of non-immunogenic RIP1-Tag2 mice with late-stage endogenous pancreatic islet carcinomas. In this study, we aimed to explore the impact of 2 Gy TBI on the treatment efficacy and the underlying mechanisms to boost CD4+ T cell-based immunotherapies. Methods: Heavily progressed RIP1-Tag2 mice underwent COMBO treatment and their survival was compared to a cohort without 2 Gy TBI. Positron emission tomography/computed tomography (PET/CT) with radiolabeled anti-CD3 monoclonal antibodies and flow cytometry were applied to investigate 2 Gy TBI-induced alterations in the biodistribution of endogenous T cells of healthy C3H mice. Migration and homing properties of Cy5-labeled adoptive Tag-Th1 cells were monitored by optical imaging and flow cytometric analyses in C3H and tumor-bearing RIP1-Tag2 mice. Splenectomy or sham-surgery of late-stage RIP1-Tag2 mice was performed before onset of COMBO treatment to elucidate the impact of the spleen on the therapy response. Results: First, we determined a significant longer survival of RIP1-Tag2 mice and an increased CD4+ T cell tumor infiltrate when 2 Gy TBI was applied in addition to Tag-Th1 cell PD-L1/LAG-3 treatment. In non-tumor-bearing C3H mice, TBI induced a moderate host lymphodepletion and a tumor antigen-independent accumulation of Tag-Th1 cells in lymphoid and non-lymphoid organs. In RIP1-Tag2, we found increased numbers of effector memory-like Tag-Th1 and endogenous CD4+ T cells in the pancreatic tumor tissue after TBI, accompanied by a tumor-specific Th1-driven immune response. Furthermore, the spleen negatively regulated T cell effector function by upregulation PD-1/LAG-3/TIM-3 immune checkpoints, providing a further rationale for this combined treatment approach. Conclusion: Low-dose TBI represents a powerful tool to foster CD4+ T cell-based cancer immunotherapies by favoring Th1-driven antitumoral immunity. As TBI is a clinically approved and well-established technique it might be an ideal addition for adoptive cell therapy with CD4+ T cells in the clinical setting. |
| Databáze: | OpenAIRE |
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