TMIC-04THERAPEUTIC ANTI-GLIOMA IMMUNITY IS DEPENDENT ON VACCINATION-INDUCED T CELL RESPONSES AND INHIBITION OF iAPC FUNCTION IN THE TUMOR MICROENVIRONMENT
Year: 2015
Type: article
Abstract: While tumor lysate-pulsed dendritic cell (DC) vaccination can cure or prolong survival in the adjuvant setting, cure rates are elusive when the tumors are well established. We hypothesized that immune suppression in malignant gliomas was dominantly mediated via the PD-1/PD-L1 mechanism by tumor-infiltrating immunosuppressive antigen presenting cells (iAPCs). To test these hypotheses, T cells were co-cultured with murine glioma cells in the presence of iAPCs harvested from tumor-bearing C57BL/6 or PDL1-KO DC vaccine-treated mice and/or inhibition of PD-1/PD-L1. T cell cytotoxicity was evaluated utilizing the xCelligence impedance analysis system in vitro. To evaluate these concepts in the in vivo setting, mice were implanted with GL261 gliomas in the brain and then treated with DC vaccination +/- PD-1 mAb blockade or a CNS-penetrant small molecule inhibitor of CSF-1R (PLX-3397, Plexxicon) and overall survival was quantified. Characterization of the intratumoral infiltrate induced by DC vaccination revealed a PD-L1+ CD11b+ CSF1r+ inhibitory antigen-presenting cell (iAPC) population. In vitro T cell cytotoxicity was significantly reduced with the addition of iAPCs to the T cell/ tumor co-culture; however, tumor cell lysis was re-established with adjuvant administration of a blocking PD-1 mAb (p < 0.01). In our in vivo treatment model, PD-1 mAb blockade in combination with tumor lysate-pulsed DC vaccination induced a highly significant therapeutic benefit to animals bearing well-established i.c. gliomas (p < 0.01). In addition, treatment with a CNS penetrant inhibitor of CSF-1R (PLX-3397), in conjunction with DC vaccination, improved the therapeutic benefit beyond that of PD-1 mAb blockade. These adjuvant treatments were dependent on CD8 T cells, as antibody removal of endogenous CD8 cells completely eliminated the therapeutic benefit. These results suggest that clinically relevant anti-tumor immunity to GBM must have at least these two cellular components: 1) significant infiltration of tumor-specific TIL; and 2) blockade of the iAPC function within the tumor microenvironment.
Source: Neuro-Oncology
Language: English
Subfield: Immunology
Field: Immunology and Microbiology
Domain: Life Sciences
Open Access status: green
OpenAlex ID: W2554612837