Boosting antitumor responses of T lymphocytes infiltrating human prostate cancers

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.

Cancer-Induced Signaling Defects in Antitumor T Cells

“…Collectively considered, one interpretation of those results is that biochemical and functional assay of signaling in T cells before permeabilization is correct (diminished calcium flux, sometimes depressed cytokine secretion, proliferation) and that apparent loss of selected signaling components (p56 lck , TCRζ) reflects artifactual degradation of protein attendant to cell lysis conditions. This notion is supported by subsequent results from multiple laboratories that showed TCRζ is particularly sensitive to proteolysis (Bronte et al, 2005;Franco et al, 1995;Gastman et al, 1999;Levey and Srivastava, 1995;Wang et al, 1995). This conclusion can also be drawn from a subsequent paper from that lab in which the kinetics of loss of TCRζ and p56 lck as a function of time of tumor growth was determined (Correa et al, 1997).…”

Peripheral T-Cell Tolerance Associated with Prostate Cancer Is Independent from CD4+CD25+ Regulatory T Cells

“…Also, inhibition of IDO by 1-MT did not revert tolerance in our transgenic model. On the other hand, high levels of nitrotyrosines in T cells infiltrating prostate cancer from humans and TRAMP mice suggested a local production of peroxynitrites (50). Indeed, in vitro inhibition of arginase and nitric oxide synthase activity restored T-cell responsiveness to tumor.…”

Tumour-released exosomes and their implications in cancer immunity

“…[11][12][13][14] Furthermore, DCs are directly affected in their specialized ability to process and present exogenous antigens through their antigen processing machinery, thereby losing their crucial ability to prime specific T cells through cross-presentation. 15 In addition to the lack of functional APCs, cancer patients are affected by the accumulation in peripheral blood and tumour sites 16,17 of myeloid precursors arrested at an immature differentiation stage, exerting active suppression on the development of specific T cell responses, and known as MSCs. 18 This series of functional aberrations affecting the myeloid compartment is deemed to be the result of multiple tumour-driven mechanisms requiring either direct interaction with tumour cells or the release of soluble factors that reach myeloid precursors in bone marrow and other tissues.…”