Elucidating the cellular mechanisms underlying adoptive cell transfer in models of glioma

Abstract Despite advances in solid tumor biology and oncology, pediatric and adult primary brain cancer and metastasis to the brain harbor dismal prognosis and poor outcomes. One avenue to overcome these clinical challenges is through developing robust immunotherapy to better target the tumor. Our group has previously shown that adoptive cellular therapy (ACT) provides therapeutic benefit against central nervous system (CNS) malignancies, namely medulloblastoma, brain stem glioma and glioblastoma. In this study, we characterized cell cycling differences of immune cellular sub-populations in peripheral lymphoid and tumor tissue compartments in vivo. ACT was conducted in orthotopic KR158 luciferase tumor-bearing mice, a syngeneic murine glioma model. Following completion of ACT, bromodeoxyuridine (BRDU) was administered to mice 12-hours prior to tissue collection and flow cytometry was utilized to measure the level of BRDU incorporation. 7-aminoactinomycin D was used in conjunction with BRDU to provide insight into all phases of the cell cycle. We observed significant differences in cycling populations of myeloid derived suppressor cells (MDSC) and T cells. In mice receiving ACT, MDSCs found in secondary lymphoid tissues were significantly more proliferative. In the tumor microenvironment (TME), proliferating MDSCs were significantly reduced compared to mice that did not receive treatment. Frequencies of proliferating CD4+ and CD8+ T-cells were significantly increased in cervical lymph node and TME, but reduced in spleen. These findings suggest that ACT changes immune cycling and migration dynamics in lymphoid tissue and TME to potentially promote antitumor T-cell responses and minimize tumor-mediated immunosuppression. 5R01NS112315-04