Abstract LB-162: Blockade of PD-L1 signaling, but not depletion of regulatory T cells, delays tumor growth in a murine pancreatic tumor model

Abstract

Abstract Pancreatic cancer is an aggressive disease with poor prognosis. Immunotherapy may be less effective in treating pancreatic tumors due to tumor-mediated suppression. Several mechanisms may contribute to immune suppression seen in mice bearing Panc02 pancreatic adenocarcinomas. We measured an increase in the percentage of CD4+CD25+foxp3+ regulatory T cells (Tregs) in the tumor and spleens of mice bearing Panc02 tumors (p<0.001 compared to non-tumor bearing mice). These Tregs were capable of suppressing antigen-specific T cell proliferation in a dose-dependent manner. Treatment of mice bearing Panc02 tumors using combination therapy with dendritic cells (DC) and anti-CD25 antibody (PC-61) did not demonstrate a delay in tumor growth or survival. As depletion of Tregs had little effect on Panc02 tumor growth, we examined another mechanism of immune suppression. We measured the expression of programmed death ligand-1 (PD-L1) on the surface of Panc02. PD-L1 plays a crucial role in inhibiting T cell responses and maintaining peripheral tolerance. PD-L1 expression has been measured on most pancreatic adenocarcinomas and may lead to down-regulation of antigen-specific T cell responses. To examine PD-L1 signaling blockade, mice bearing Panc02 tumors were treated with anti-PD-L1 antibody at 3 day intervals. After 3 weeks, mice receiving anti-PD-L1 antibody displayed smaller tumors than mice receiving control antibody (134 mm2 vs 221mm2 respectively, p<0.05). Splenocytes from PD-L1 treated mice secreted IFN-gamma in response to restimulation with Panc02 (p<0.01 compared to control treated mice). Furthermore, treatment with anti-PD-L1 antibody in Panc02-bearing athymic nude mice had no effect on tumor growth, indicating that treatment is T cell dependent. Survival benefit was measured in tumor-bearing mice when anti-PD-L1 antibody treatment was combined with DC immunizations (35% survival on day 75 compared to 0% in all control groups, p<0.05). To enhance this treatment, we examined combination therapy with DC, anti-PD-L1 and PC-61 antibodies. Depletion of Tregs did not enhance therapy with DC and anti-PD-L1 antibody. Together, these studies show that blockade of PD-L1 signaling inhibited tumor growth in mice with pancreatic cancer. Depletion of Tregs alone or in combination with PD-L1 blockade demonstrated no benefit in this model. Studies to optimize combination therapy using anti-PD-L1 antibody and DC-based vaccines are ongoing. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr LB-162. doi:10.1158/1538-7445.AM2011-LB-162