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Bacteria-Derived Nanobody-Decorated Nanoplatform Restores T Cell Immunity Post-Radiotherapy
Jinzhou Cai1, Xiangming Han1, Yu Zhang1
1Department of Pathology, The First Affiliated Hospital, State Key Laboratory of Radiation Medicine and Protection, School of Radiation Medicine and Protection & School for Radiological and Interdisciplinary Sciences (RAD-X), Collaborative Innovation Center of Radiation Medicine of Jiangsu Higher Education Institutions, Cancer Institute, Suzhou Medical College, Soochow University, Suzhou, Jiangsu 215123, China.
Radiotherapy can exhaust T cells by disrupting arginine metabolism and upregulating PD-L1. A novel biomimetic immunomodulator (arg/Bnb-L) reverses this, enhancing T cell function and improving radioimmunotherapy outcomes.
Area of Science:
- Immunology
- Cancer Research
- Nanomedicine
Background:
- T cell exhaustion in the tumor immune microenvironment (TIME) limits radioimmunotherapy effectiveness.
- X-ray radiotherapy can induce arginine metabolic dysregulation and PD-L1 upregulation in the tumor microenvironment (TME), leading to T cell suppression and exhaustion.
- This immunosuppression hinders the body's natural anti-tumor immune response.
Purpose of the Study:
- To investigate the mechanisms by which radiotherapy induces T cell exhaustion.
- To develop a novel biomimetic hybrid immunomodulator (arg/Bnb-L) to overcome radiotherapy-induced immunosuppression.
- To evaluate the efficacy of combining arg/Bnb-L with radiotherapy in preclinical cancer models.
Main Methods:
- Demonstrated radiotherapy's impact on arginine metabolism and PD-L1 expression in the TME.
- Engineered a biomimetic hybrid immunomodulator (arg/Bnb-L) using bacterial membranes displaying PD-L1 nanobodies and arginine-loaded liposomes.
- Assessed the combined effects of arg/Bnb-L and radiotherapy on T cell infiltration, exhaustion markers, cytotoxic T lymphocyte function, tumor progression, and metastasis in murine models.
Main Results:
- Radiotherapy was shown to induce arginine metabolic dysregulation and PD-L1 upregulation, promoting T cell exhaustion (PD-1+TIM-3+).
- The arg/Bnb-L nanoplatform effectively blocked PD-1/PD-L1 signaling, restored T cell metabolism, and promoted dendritic cell maturation.
- Combination therapy significantly increased CD8+ T cell infiltration, reduced exhausted T cells, preserved cytotoxic T lymphocyte function, and inhibited tumor growth and metastasis.
Conclusions:
- Radiotherapy induces immunosuppression via dual mechanisms: arginine metabolic dysregulation and PD-L1 upregulation.
- The biomimetic immunomodulator arg/Bnb-L represents a promising strategy to enhance radioimmunotherapy by reprogramming the tumor immune microenvironment.
- Targeted metabolic and immunologic reprogramming offers a novel approach to improve cancer treatment outcomes.
