Dominance of CD4+ lymphocytic infiltrates with disturbed effector cell characteristics in the tumor microenvironment of prostate carcinoma

Abstract

Prostate cancer is the most common cancer of men in the Western world. Despite the over-expression of tumor-associated antigens, like PSA or PSMA, immune activation is inefficient. The goal of this investigation was to assess in situ characteristics of prostate cancer-infiltrating lymphocytes and to determine their activation status and effector function. We compared 17 carcinoma containing tissues, four benign prostatic hyperplasia tissues and eight healthy prostate tissues regarding lymphocyte subset composition, locoregional distribution, and functional status using immunohistological staining of cryopreserved tissues. For determination of lymphocyte subsets, serial sections were stained with CD3, CD4, and CD8 antibodies. Activation status and effector function were studied using CD69, interferon-gamma (IFN gamma), perforin, and CD3 zeta chain antibodies. T-cell-receptor repertoire (TCR) analysis was made to determine the complexity of infiltrating lymphocytes. CD3+, CD4+, and CD69+ T lymphocytes were prominent in tissues derived from patients with prostate carcinoma. CD8+ lymphocytes were significantly less than CD4+ lymphocytes. IFN gamma and perforin were downregulated on infiltrating lymphocytes compared to cells of healthy prostate tissue. Very few lymphocytes were detected within cancerous lesions whereas surrounding tissues showed extensive lymphocyte cluster formation. The TCR repertoire of infiltrating lymphocytes was broad and similar to that of healthy prostate tissue, giving no evidence for specific lymphocyte recruitment. In the prostate cancer microenvironment, CD4+ T lymphocytes dominated while CD8+ T cells were sparse. The lymphocytes exhibited signs of disturbed effector function. Consequently, the immune response against autologous tumor cells is likely to be inefficient in controlling tumor growth.