Abstract A67: Increased circulating HLA-DRneg, Lin1 lo/neg, CD33+ CD11b+ myeloidderived suppressor cells correlate with increased arginase levels in patients with prostate cancer

Abstract

Due to our increased understanding of tumor immunology a number of immunotherapeutic approaches have been successfully introduced into the clinic and further promising therapeutic strategies are being investigated in on-going clinical trials. However, evaluation of anti-tumor immunity in such trials as in animal models has shown that tumor escape from immune recognition and tumor-mediated suppression of anti-tumor immunity can pose a significant obstacle to successful cancer therapy. One of the main cell types that have emerged as potent suppressors of T cell-mediated immunity are myeloid derived suppressor cells (MDSCs). MDSCs are a heterogeneous population of immature cells of myeloid origin with a wide repertoire of effector mechanisms. While there are published data on circulating MDSC in cancer patients with diverse primary tumors, there is little published data investigating MDSCs specifically in prostate cancer. Following on from our recent study looking at HLADR- Lin1low/− CD33+ CD11b+ MDSCs in pancreatic, esophageal and gastric cancer patients we sought to determine whether this population of MDSCs also played a role in prostate cancer. Peripheral blood was collected from 75 prostate cancer patients and 50 healthy controls. PBMC were harvested with subsequent flow cytometric analysis of MDSC. MDSCs were highly statistically significantly elevated in prostate cancer patients compared with healthy controls (p<0.0001). In this cohort there was no evidence of increasing MDSC % with stage of disease. MDSCs exert their immunosuppressive activity through multiple mechanisms, including arginine depletion. MDSC expressing arginase I deplete L-arginine from the microenvironment and profoundly inhibit T-cell function. Analysis of arginase I levels by ELISA on the plasma from the same prostate cancer patient cohort showed that Arginase I levels were also highly statistically significantly elevated in prostate cancer patients compared with controls (p<0.0001). There was a clear association between increasing Arginase I level and increasing MDSC percentage (p=0.0195). In contrast to our finding in upper gastrointestinal cancers where significant elevations of the Th2 cytokine interleukin-13 (IL-13) were found and correlated with MDSC levels, we were unable to detect IL-13 in the plasma of prostate cancer patients. This probably reflects the diverse combinations of cytokines produced by different tumors and the large number of potential MDSC-inducing and MDSC activating factors. These data not only add to our understanding of the immunobiology of prostate cancer but provide the rationale for combining immunotherapy studies with MDSC inhibition strategies. Citation Format: Nicola Annels, Rachel Gabitass, Gary Middleton, Hardev Pandha. Increased circulating HLA-DRneg, Lin1 lo/neg, CD33+ CD11b+ myeloidderived suppressor cells correlate with increased arginase levels in patients with prostate cancer [abstract]. In: Proceedings of the AACR Special Conference on Advances in Prostate Cancer Research; 2012 Feb 6-9; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2012;72(4 Suppl):Abstract nr A67.