Androgen Deprivation Boosts Prostatic Infiltration of Cytotoxic and Regulatory T Lymphocytes and Has No Effect on Disease-Free Survival in Prostate Cancer Patients

Abstract

Purpose: The value of neoadjuvant hormone therapy (NHT) prior to radical prostatectomy as a means of restraining prostate cancer (PCa) and strengthening its immunotherapy is still uncertain. This article asks whether it subverts immunoregulatory pathways governing tumor microenvironments, and has an impact on patient outcome.Experimental Design: We microdissected epithelium and stroma from cancerous and normal prostate specimens from 126 prostatectomized patients, of whom 76 had received NHT, to detect cytokine/ chemokine gene expression levels by real-time reverse transcriptase PCR. Confocal microscopy was used to identify cytokine/chemokine cell sources, and immunostainings to characterize lymphocyte subsets whose prognostic effects were assessed by Kaplan-Meier analyses.Results: NHT boosted the expression of IL-7 in the stroma and that of IFNg-inducible protein-10/ CXCL10 in the glandular epithelium of normal prostate tissue, and restored the CD8 þ lymphocyte depletion occurring in PCa, whereas it significantly increased the CD4 þ lymphocyte infiltrate. Lymphocytes, mostly with CD8 þ phenotype, expressed the T-cell intracellular antigen-1, granzyme-B, and perforin, typical of cytotoxic-effector T cells. NHT also induced thymus and activation-regulated chemokine/CCL17 production by monocytes/macrophages in the prostate and draining lymph nodes, and increased the number of their Forkhead box P3 (Foxp3)the lack of association (P ¼ 0.27) between NHT and the high intratumoral CD8 þ /Treg ratio indicative of a good prognosis.Conclusions: Androgen withdrawal regulates cytokine/chemokine gene expression in normal prostate and lymphoid tissues, and this probably favors both CD8 þ and Treg infiltrates, leaves their intratumoral balance unchanged, and thus has no impact on disease-free survival.

Heterogeneity in the inter-tumor transcriptome of high risk prostate cancer

“…This effect is in stark contrast to the frequent observation of AR reactivation in castration-resistant prostate cancer; which is often concomitant with the overexpression of de novo steroidogenic enzymes [9]. Upregulated genes in NHT tumors were linked to growth suppression and increased apoptosis (for example, DUSP2, DUSP4, CCDC8, TNS4) and also with cytotoxic T lymphocytes (for example, CD8A, GZMK), with the latter in line with previous reports demonstrating an increase in prostatic infiltration of lymphocytes post-hormone treatment [10,11]. However, although the data suggested that most tumors were responding to androgen deprivation therapy at the time of tumor collection, four tumors displayed elevated CHGA expression at the mRNA level ( Figure 1D).…”

CD73 Expression Is an Independent Prognostic Factor in Prostate Cancer

“…In prostate cancer, however, the prognostic value of tumor-infiltrating lymphocytes has long been unclear. Earlier studies reported that prostate tumor-infiltrating lymphocytes were either not associated with prognosis or associated with better outcomes (8)(9)(10). Recent studies in large cohorts have however challenged this notion.…”

“…Because androgen ablation is associated with an increased production of TGFb in the prostate, CD73 may also be induced by androgen deprivation therapy (ADT). This possibility merits further investigation, especially considering that ADT is known to increase prostatic T-cell infiltration without affecting clinical outcomes (46)(47).…”

“…The presence of tumor-infiltrating CD8 þ T cells, for instance, has been associated with a favorable prognosis in various types of cancer (6). In prostate cancer, Vesalainen and colleagues (8) and Sorrentino and colleagues (9) reported that high levels of tumor-infiltrating CD8 þ T cells were associated with improved disease-free survival. In contrast, K€ arj€ a and colleagues (10) showed that high lymphocytic densities were associated with shorter recurrence-free survival.…”

Interleukin-30 Expression in Prostate Cancer and Its Draining Lymph Nodes Correlates with Advanced Grade and Stage

“…For immunohistochemistry (IHC), formalin-fixed, paraffin-embedded sections were treated with H 2 O 2 /3% for 5 minutes to inhibit endogenous peroxidase and then washed (24).…”