Pten Null Prostate Epithelium Promotes Localized Myeloid-Derived Suppressor Cell Expansion and Immune Suppression during Tumor Initiation and Progression

Abstract

Chronic inflammation is known to be associated with prostate cancer development, but how epithelium-associated cancer-initiating events cross talk to inflammatory cells during prostate cancer initiation and progression is largely unknown. Using the Pten null murine prostate cancer model, we show an expansion of Gr-1⁺ CD11b⁺ myeloid-derived suppressor cells (MDSCs) occurring intraprostatically immediately following epithelium-specific Pten deletion without expansion in hematopoietic tissues. This MDSC expansion is accompanied by sustained immune suppression. Prostatic Gr-1⁺ CD11b⁺ cells, but not those isolated from the spleen of the same tumor-bearing mice, suppress T cell proliferation and express high levels of Arginase 1 and iNOS. Mechanistically, the loss of PTEN in the epithelium leads to a significant upregulation of genes within the inflammatory response and cytokine-cytokine receptor interaction pathways, including Csf1 and Il1b, two genes known to induce MDSC expansion and immunosuppressive activities. Treatment of Pten null mice with the selective CSF-1 receptor inhibitor GW2580 decreases MDSC infiltration and relieves the associated immunosuppressive phenotype. Our study indicates that epithelium-associated tumor-initiating events trigger the secretion of inflammatory cytokines and promote localized MDSC expansion and immune suppression, thereby promoting tumor progression.

View correction statement:

Erratum for Garcia et al., Pten Null Prostate Epithelium Promotes Localized Myeloid-Derived Suppressor Cell Expansion and Immune Suppression during Tumor Initiation and Progression

ACKNOWLEDGMENTS

We thank colleagues in our laboratories for suggestions and comments. We thank Dapei Li for microdissection assistance and Ilsa Coleman for assistance with the analysis of microarray data.

A.J.G. was supported by an NIH minority supplement award (R01 CA107166S); M.R. and L.M.T. were supported by NIH grant T32 CA009056. This work has been supported in part by awards from the Prostate Cancer Foundation (to H.W. and P.S.N.), a DOD idea development award (to H.W.), and grants from the NIH (R01 CA107166 and RO1 CA121110 to H.W., UO1 CA164188 to H.W. and P.S.N., R01 CA165573 P.S.N., and P50CA097186 to P.S.N.).

We have no conflicting interests to disclose.