Abstract LB-148: Depletion of myeloid derived suppressor cells in pancreatric cancer results in decreased tumor growth

Abstract

Abstract Introduction: Pancreatic adenocarcinoma (PA) is a highly aggressive and chemo-resistant malignancy with a median survival of only 6 months. Myeloid derived suppressor cells (MDSC) have been implicated in the immune suppression and growth of several malignancies. MDSC are highly prevalent in the tumor microenvironment, and represent a potential therapeutic target. Here, we assess the tumor-promoting ability of MDSC in a model of PA and explore MDSC targeting strategies using ZA, a drug known to inhibit MDSC. Methods: C57BL/6 mice were inoculated in the right flank with 100,000 or 50,000 of the syngeneic PA line, Pan02. Tumor volume was determined by standard calculation using caliper measurements. Mice were treated with Gemcitabine 20mg/kg Qwk IP and/or ZA 1ug QOD SQ once tumors were palpable. Analysis for MDSC accumulation was determined in the tumor, spleen and bone marrow of mice at sacrifice using flow cytometry for standard markers of MDSC (CD45, CD11b, Gr1, Ly6G, and Ly6C). MDSC prevalence is expressed as a percentage of total leukocytes (CD45+). Statistical analysis was performed using non-parametric student's t-test. Results: MDSC are up regulated in the spleen and bone marrow of mice with flank injected Pan02 compared to non-tumor bearing mice. MDSC accumulate over time and increase in number until 4 weeks post-inoculation (CD45 + 11b+Gr1+, Bone Marrow: 26.06% 42.04%, spleen 1.07% 7.18%, p=0.0021). Treatment of tumor bearing mice with ZA decreases tumor associated MDSC (CD45+11b+Gr1+: 50.36 29.38; CD45+11b+Ly6G+: 49.45 30.47) and tumor volume (2.45 1.71 p=0.034). ZA also works in concert with Gemcitabine to decrease MDSC (Gr1 +: 50.36 39.38; Ly6G+: 49.45 37.28;) and tumor volume (2.45 1.02, p=0.0011). Conclusion: MDSC play an integral role in the development of PA. Depletion of MDSC by ZA results in significantly smaller tumors and can be added to the standard chemotherapeutic regimen (Gemcitabine) successfully. The addition of ZA to Gemcitabine represents an attractive and innovative regimen to improve the treatment of this deadly malignancy. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr LB-148.