Up‐regulation of proliferative and migratory genes in regulatory T cells from patients with metastatic castration‐resistant prostate cancer

Abstract

A higher frequency of regulatory T cells (Tregs) has been observed in peripheral blood mononuclear cells (PBMC) of patients with different types of solid tumors and hematological malignancies as compared to healthy donors. In prostate cancer patients, Tregs in PBMC have been shown to have increased suppressive function. Tumor-induced biological changes in Tregs may enable tumor cells to escape immunosurveillance. We performed genome-wide expression analyses comparing the expression levels of more than 38,500 genes in Tregs with similar suppressive activity, isolated from the peripheral blood of healthy donors and patients with metastatic castration-resistant prostate cancer (mCRPC). The differentially expressed genes in mCRPC Tregs are involved in cell cycle processes, cellular growth and proliferation, immune responses, hematological system development and function, and the IL-2 and TGF-β pathways. Studies revealed that the levels of expression of genes responsible for T-cell proliferation (C-FOS, C-JUN, and DUSP1) and cellular migration (RGS1) were greater in Tregs from mCRPC patients as compared to values observed in healthy donors. Increased RGS1 expression in Tregs from mCRPC patients suggests a decrease in these Tregs’ migratory ability. Additionally, the higher frequency of CD4+CD25highCD127− Tregs in the peripheral blood of mCRPC patients may be the result of an increase in Treg proliferation capacity. Results also suggest that the alterations observed in gene expression profiles of Tregs in mCRPC patients may be part of the mechanism of tumor escape from host immune surveillance.

Immunohistochemical expression of interleukin-2 receptor and interleukin-6 in patients with prostate cancer and benign prostatic hyperplasia: Association with asymptomatic inflammatory prostatitis NIH category IV

“…In prostate cancer patients, increased CD4 + CD25 + regulatory T cells (Treg cells) are found in tumour tissue as well as in serum at the time of radical prostatectomy or in the castration-resistant stage with metastases. These Treg cells hinder the body's own immune activity of T cells against the tumour [18,[33][34][35]. In prostate cancer, the growth, migration and adhesion of prostate cancer cells are reinforced by the effect of IL-6 on androgen receptors [19].…”

Inflammatory macrophage–associated 3-gene signature predicts subclinical allograft injury and graft survival

“…Other groups have investigated intragraft macrophages, though many investigations have focused on murine models of cardiac transplantation (34)(35)(36). Wu et al interrogated macrophage polarization in transplant rejection (35) and found that graft-infiltrating macrophages in a murine model of chronic cardiac transplant rejection demonstrated an M2 (IL-4) phenotype; they reported that blocking the recep- tor P2X7, which may be upregulated in M2 macrophages, improved long-term cardiac allograft survival.…”

Regulators of G-Protein-Signaling Proteins: Negative Modulators of G-Protein-Coupled Receptor Signaling

“…Among the RGS proteins that modulate the function of heterotrimeric G proteins by stimulating the GTPase activity of G-protein a subunits, RGS10, a 20-kDa protein identified in 1996 by Hunt and coworkers, enhances the GTP hydrolytic activity of several members of the Ga i family, including Ga i3 , Ga q , and Ga z , but fails to associate with the structurally and functionally different Ga s subunit (Hunt et al, 1996;Popov et al, 1997). RGS10 belongs to the R12 subfamily of RGSs and shares with other RGS proteins the conserved 120 amino acid sequence termed the RGS domain, which, in the case of RGS10, has been reported to be fully active per se, showing a similar GAP activity than the full-length RGS10 (Ali et al, 2013;Cacan et al, 2014;Intini et al, 2014;Lee et al, 2012a;Mao et al, 2014;Popov et al, 1997;Rivero et al, 2013).…”

“…T-cell-dependent antigens produced a delayed antibody response in RGS1 knockout mice . RGS1 has been shown to be involved in chemokine-mediated homing of lymphocytes to secondary lymphoid organs, such as the intestinal mucosa, as well as their localization and movement within lymphoid organ during the immune response (Gibbons et al, 2011;Huen et al, 2013;Wierenga et al, 2014).…”