Abstract
Background
One major challenge in glioma immunotherapy is to ensure homing of peripherally activated adaptive immune cells to the tumor while retaining their effector function. For systemic tumors, local irradiation has been shown to induce a proinflammatory chemokine and cytokine milieu which facilitates tumor infiltration of effector immune cells. Within the CNS, molecular mechanisms mediating the irradiation-induced modulation of leukocyte function are only poorly understood but essential to exploit radiotherapy as immunological adjuvant for malignant gliomas.
Material and Methods
To assess the influence of radiotherapy on the outcome of T-cell-based immunotherapeutic approaches for brain tumors we have created a syngeneic murine GL261-glioma model over-expressing the major histocompatibility complex (MHC) class I-restricted model-antigen glycoprotein-100 (gp100), which is expressed in about 50% of human glioblastomas.
Results
Low-dose glioma irradiation (4x2Gy) resulted in increased numbers of vaccination-induced and adoptively transferred gp100-specific tumor-infiltrating T cells. Cytotoxic T cells displayed an activated phenotype and combined radioimmunotherapy significantly inhibited growth of established gliomas. In vivo two-photon-microscopy and correlative ultramicroscopy of ex vivo cleared whole brains demonstrated co-localization of fluorescently labeled tumor blood vessels with adoptively transferred T cells after radiotherapy. Of note, chemokine arrays and immunohistochemical analyses suggested the induction of CXCL10 in the tumor tissue as an important mechanism of irradiation-mediated recruitment of antigen-specific T cells to gliomas.
Conclusion
Low-dose glioma irradiation promotes infiltration of vaccination-induced or adoptively transferred tumor-specific cytotoxic T cells and thus synergizes with T cell-based immunotherapies.