Abstract 3545: Neutrophils regulate effector and inhibitory T cell function in prostate cancer

Proceedings: AACR 103rd Annual Meeting 2012‐‐ Mar 31‐Apr 4, 2012; Chicago, IL A significant number of patients develop castration-resistant prostate cancer, for which there is no cure. Our goal is to characterize the effector and inhibitory mechanisms which modulate prostate cancer progression. We have previously shown that CD8+ effector function is transiently increased following castration of prostate-specific Pten-/- mice. To determine inhibitory mechanisms responsible for the transient increase in effector function, we evaluated the role of myeloid cells in this model. We observed a heavy Gr-1+ cell infiltrate in the primary tumors which was markedly increased early after castration. Phenotypic profiling of tumor-infiltrating Gr-1+ cells from intact and castrated mice showed uniform CD11b+Ly6C+Ly6G+ marker expression and neutrophil morphology. To determine the functional importance of these tumor-associated neutrophils (TANs), we administered anti-Ly6G antibody to intact Pten-/- mice. We found that depletion of TANs slightly increased tumor burden prior to castration. In addition, the number of regulatory T cells was elevated in the tumor after neutrophil depletion, and the proportion of functional CD8+ T cells was unchanged. In contrast, concomitant castration and neutrophil depletion did not change tumor weight, early (2.5 wk) or late (5 wk) after castration. Although the total number of CD8+ T cells in the tumor was increased by neutrophil depletion early after castration, the proportion of functional CD8+ T cells was unchanged. A striking increase in regulatory T cell (Treg) numbers was also observed. In contrast, the number of CD8+ T cells and the percentage of functional cells were increased late after castration and neutrophil depletion. Furthermore, depletion of neutrophils decreased intratumoral Tregs at 5 weeks post-castration. These data suggest that TANs modulate the tumor microenvironment, rendering it increasingly immunosuppressive late after castration. We have found that castration increases systemic Tregs in Pten-/- mice. To determine whether Tregs regulate neutrophil function in prostate tumors, we administered α-CD25 antibody along with castration. Neutrophil numbers in castration-resistant prostate tumors increased, and expression of TNFα, IL4Rα, iNOS, Arg, IL-6 and IL-12 by the neutrophils was also augmented. Concomitantly, an increase in the proportion of functional CD8+ T cells was observed. Interestingly, depletion of neutrophils abrogated the augmentation of CD8+ CTL activation following Treg depletion, suggesting that cross-talk between neutrophils and Tregs regulates CD8 effector function. Thus, TANs in Pten-/- prostate tumors have anti-tumor potential and can modulate both CD8+ effector T cells and Tregs within the tumor. Our long-term goal is to understand how TANs control effector and inhibitory arms of the immune system in order to improve outcomes following immunotherapy. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3545. doi:1538-7445.AM2012-3545