Modulators of Arginine Metabolism Do Not Impact on Peripheral T-Cell Tolerance and Disease Progression in a Model of Spontaneous Prostate Cancer

Abstract

Purpose: Chronic inflammation, recruitment of myeloid-derived cells, and perturbation of the arginine metabolism have been all proposed as mechanisms favoring prostate carcinogenesis and tumor immunoescape. Objective of this study was to evaluate whether accumulation of CD11b þ Gr1þ cells, also defined myeloid-derived suppressor cells, occur in mice affected by transplantable or spontaneous prostate cancer (PC). We also investigated whether N(G) nitro-L-arginine methyl ester (L-NAME) and sildenafil, both modulators of the arginine metabolism, restrain tumor growth and restore tumor-specific immunity.Experimental Design: Wild-type C57BL/6 mice bearing TRAMP-C1 PC and transgenic adenocarcinoma of the mouse prostate (TRAMP) mice were treated with vehicle, L-NAME or sildenafil, and evaluated for CD11b þ cells accumulation in the blood, several organs, and the tumor mass and for disease progression.organs and especially in the tumor of the two mouse models. L-NAME and sildenafil impaired the immunosuppressive function of CD11b þ cells in both models and restrained TRAMP-C1 growth, but they neither break tumor-specific immune tolerance nor limit tumor progression in TRAMP mice. Conclusions: Collectively, our results emphasize substantial differences in tumor-induced alteration of myelopoiesis and sensitivity to modulators of the arginine metabolism between a transplantable and a spontaneous model of PC. They also suggest that perturbation of the arginine metabolism is dispensable for PC progression and the associated T-cell tolerance.

Tenascin-C Protects Cancer Stem–like Cells from Immune Surveillance by Arresting T-cell Activation

“…Indeed, CSC and/or other more differentiated tumor cells may generate immunosuppressive networks within the primary lesion, and anergic Tag-specific CD8 þ T cells are found in the prostate of TRAMP mice (14). Both regulatory T cells and myeloid-derived suppressor cells accumulate in the prostate of cancer patients and TRAMP mice, although their targeting revealed insufficient for breaking T-cell tolerance and sustaining antitumor immunity (46,47). Moreover, in TRAMP and in human prostate cancer lesions, a population of tolerogenic DCs induces CD8 þ T cells to acquire suppressive functions through indoleamine-2,3-dioxygenase, arginase, TGFb, and PDL-1 (48).…”

The Role of Inflammation in Prostate Cancer

“…MDSCs accumulate in the tumor microenvironment as well as the blood, lymph nodes, and bone marrow in association with several forms of human cancer and may contribute to tumor immune escape due to their general functional role in immune suppression (Ostrand-Rosenberg and Sinha 2009). In regard to prostate cancer, multiple murine models of prostate cancer demonstrate accumulation of MDSCs in tumors along with a potential contribution to tumor progression (Wu et al 2012;Svensson et al 2011;Rigamonti et al 2011). …”

CD73-Deficient Mice Are Resistant to Carcinogenesis

“…TRAMP-C1 mouse tumor cell lines were maintained as previously described (18). MCA.WT100-5 and MCA.WT100-7 cells were derived from WT mice that had been inoculated with 100 mg of 3-methylcholanthrene (MCA).…”

“…Previous studies suggested that CD73 is associated with malignant transformation of prostate epithelial cells (20). TRAMP transgenic mice develop mild to severe prostate hyperplasia by 12 weeks of age and by 24 weeks of age, approximately 100% of male mice have poorly differentiated and invasive adenocarcinomas (18). We generated CD73 À/À TRAMP transgenic mice and compared prostate weights with CD73 þ/þ TRAMP mice.…”