Tmic-16. tumor-infiltrating myeloid cells mediate adaptive immune resistance in glioblastoma

In this study, we identified a tumor-infiltrating Ly6-C+ CD11b+ myeloid (TIM) cell population that expands in response to DC vaccine treatment and significantly expresses PD-L1 in both our murine model and patient GBM samples. We hypothesized that this cell population is dominantly responsible for mitigating the immune response. To evaluate this, we administered tumor lysate-pulsed DC vaccine treatment to mice bearing intracranial murine GL261 tumor. Mice were randomized into treatment groups receiving PD-1 mAb, Ly6-C depleting mAb, or both. Following treatments, we euthanized mice and harvested tumor-bearing brain hemisphere for analysis. We noted that the TIL population was significantly activated in mice that had received PD-1 mAb or Ly6-C depleting mAb. There was no additional activation in groups receiving both treatments. These results were recapitulated in an in vitro cytotoxicity assay, with TIM inhibition of TIL cytolysis of tumor cells significantly reduced with PD-1 mAb blockade. To target TIMs in vivo with a clinically-relevant treatment, we next evaluated the use of colony stimulating factor-1 receptor inhibitor (CSF-1Ri, PLX3397), a drug already in clinical trials, instead of Ly6-C depleting mAb. Treatment with PLX3397 reduced the TIM population and promoted expression of key chemotactic factors associated with increased TIL infiltration in remaining TIMs. When combined with PD-1 mAb blockade, PLX3397 resulted in increased the number of TILs and their activation...
Source: Neuro-Oncology - Category: Cancer & Oncology Authors: Tags: TUMOR MICROENVIRONMENT Source Type: research