IMMUNOTHERAPY/VACCINE THERAPY (CLINICAL AND/OR LABORATORY RESEARCH)

摘要

Recent work has demonstrated that the interaction of the Programed Death-1 (PD1) negative costimulatory molecule with its ligand, PDL1 in the tumor microenvironment, plays an immunoregulatory role that may prevent the development of a successful anti-tumor response. We hypothesized that dendritic cell vaccination (DCVax) would induce a compensatory upregula-tion of PDL1 within the tumor microenvironment as a result of increased tumor infiltrating lymphocytes (TILs). We also hypothesized that simultaneous blockade of the PD1/ PDL1 interaction would promote a successful anti-tumor response. To test this, immunocompetent C57BL/6 mice were implanted with GL261 glioma cells in the brain. Mice were then stratified into 4 treatment groups (Tx on days 3 and 13 post-implant): (1) Control; (2) IP murine anti-PD1 mAb (10mg/kg) only; (3) subcutaneous GL261 lysate-pulsed DCVax only; and (4) combination (anti-PD1 mAb plus DCVax). Overall survival was quantified. On post-implant days 15 and 20, mice were imaged using a Bruker 7T MR scanner to obtain anatomical, perfusion, and pH-weighted data. On post-implant days 16 and 21, mice were imaged with [18F]-FAC PET to evaluate the lymphocyte response. Tumor-bearing hemisphere, spleen, and lymph node (LN) leukocytes were then harvested, processed, and stained for FACS analysis. Median survival of the combination group was significantly greater than the DCVax or PD-1 treatment groups (p ＜ 0.005). MRI showed decreased tumor volume and inflammation in the combination group. FACS analysis and [18F]-PET demonstrated significantly enhanced numbers of activated lymphocytes accumulating within the cervical LN and tumor in PD-1 mAb, DCVax, and combination treatment groups. Elevated PDL1 expression on tumor-associated APCs was also noted in the DCVax group, but specifically lower in the combination group. We propose that PDL1 is upregulated within the tumor in response to immunotherapy, but can be blocked to restore effective anti-tumor immune responses.