Defining the Synergistic Effects of Irradiation and T-Cell Immunotherapy for Murine Intracranial Tumors

Abstract

In recent studies, we demonstrated that the systemic adoptive transfer of tumor-draining lymph node (LN) cells, activatedex vivowith anti-CD3 mAb or bacterial superantigens, was effective for treatment of tumors in the brain, an immunologically privileged site. In this study, we demonstrate that sublethal whole body irradiation (WBI) or local cranial irradiation of the tumor-bearing host prior to the adoptive transfer of LN cells, activated with the superantigen, SEC2, augments therapeutic efficacy, whereas body irradiation with cranial shielding is ineffective. WBI prior to tumor inoculation or treatment of tumor-bearing animals with cyclophosphamide to eliminate suppressor cells did not enhance the therapeutic efficacy of adoptively transferred cells. Analysis of brains by immunohistochemistry, 4 days after cell transfer, revealed a dense infiltrate of SEC2-activated T lymphocytes which exclusively express the T cell receptor Vβ8.2 phenotype, of both CD4 and CD8 subsets, throughout the tumors in both irradiated and nonirradiated animals. In addition, MAC-1+cells were present within tumors irrespective of either irradiation or cell transfer. These findings demonstrate that the systemically transferred T cells could gain access to the tumor located in the CNS. However, the therapeutic enhancement by sublethal irradiation does not reflect an increase in T cell or MAC-1+cell migration into the tumor.