Abstract
Immunotherapy may provide valid alternative therapy for patients with hormone-refractory metastatic prostate cancer. However, if the tumor environment exerts a suppressive action on antigen-specific tumor-infiltrating lymphocytes (TIL), immunotherapy will achieve little, if any, success. In this study, we analyzed the modulation of TIL responses by the tumor environment using collagen gel matrix–supported organ cultures of human prostate carcinomas. Our results indicate that human prostatic adenocarcinomas are infiltrated by terminally differentiated cytotoxic T lymphocytes that are, however, in an unresponsive status. We demonstrate the presence of high levels of nitrotyrosines in prostatic TIL, suggesting a local production of peroxynitrites. By inhibiting the activity of arginase and nitric oxide synthase, key enzymes of L-arginine metabolism that are highly expressed in malignant but not in normal prostates, reduced tyrosine nitration and restoration of TIL responsiveness to tumor were achieved. The metabolic control exerted by the tumor on TIL function was confirmed in a transgenic mouse prostate model, which exhibits similarities with human prostate cancer. These results identify a novel and dominant mechanism by which cancers induce immunosuppression in situ and suggest novel strategies for tumor immunotherapy.
Highlights
Human tumors express antigens recognized by T and B lymphocytes, a recent discovery that has paved the way for the development of novel immunotherapeutic strategies targeting the immune effectors toward cancer-associated antigens [1, 2]
Phenotypic analysis of prostate tumor-infiltrating lymphocytes To characterize the phenotype of T lymphocytes infiltrating human prostate carcinoma (PCa), prostate samples obtained from untreated patients who underwent radical prostatectomy for PCa were analyzed by FACS (BD Biosciences) analysis and immunohistochemistry
Initial studies revealed that tumor-infiltrating lymphocytes (TIL) infiltrating PCa samples were mainly CD8ϩ T lymphocytes (Fig. 1, A and B); the following experiments were focused on CD8ϩ TIL
Summary
Human tumors express antigens recognized by T and B lymphocytes, a recent discovery that has paved the way for the development of novel immunotherapeutic strategies targeting the immune effectors toward cancer-associated antigens [1, 2]. Some tumor nodules regress or disappear, whereas in the same patient others progress The reasons for this heterogeneous response are not clear, but it was proposed that tumor nodules might have different permissive states toward the activity of anti-tumor lymphocytes [7]. The interactions between lymphocytes, tumors, and tumor-infiltrating myeloid cells can create a number of functional events that range from full activation of specific immune responses to the induction of tolerance in tumor-specific T lymphocytes [8, 9]. Tryptophan is not the only amino acid whose metabolism is increased in a tumor-conditioned microenvironment, and numerous reports suggest a role for the activation of L-arginine (L-Arg) metabolizing enzymes during tumor growth and development. NOS2 oxidizes L-Arg to citrulline and nitric oxide (NO), a pleiotropic molecule important for ischemia, inflammation, angiogenesis, immune response, and cell growth and differentiation [14]
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