Suppressive Effect Of Treg Cells Research Articles

Immunomodulatory and anticancer effects of intra-tumoral co-delivery of synthetic lipid A adjuvant and STAT3 inhibitor, JSI-124

The efficiency of cancer immunotherapy strategies is hampered by the existence of an intra-tumoral immunosuppressive environment involving tolerogenic dendritic cells (DCs) and regulatory T (Treg) cells. Hyperactivation of STAT3 in tumor is implicated in the generation of this immunosuppressive environment. The purpose of this study was to test whether simultaneous inhibition of STAT3 in tumor and TLR4 ligand-induced activation of DCs can modulate tumor-induced immunosuppression. For this purpose, the effects of a TLR4 ligand, 7-acyl lipid A, delivered by poly(lactic-co-glycolic acid) nanoparticles (PLGA-NPs) to DCs on the activity of DCs and Treg cells was evaluated in vitro. In addition the immunomodulatory and anticancer effects of 7-acyl lipid A PLGA-NPs in combination with a STAT3 inhibitory agent, JSI-124, in a B16 mouse melanoma model was explored, in vivo. PLGA-NP delivery of 7-acyl lipid A to DCs reduced the suppressive effects of Treg cells on T cells in vitro. Besides, daily Intra-tumoral co-administration of 7-acyl lipid A PLGA-NPs and JSI-124 in C57BL/6 mice bearing B16-F10 tumor for 8 days resulted in a significant increase in the percentage of tumor infiltrated T cells as compared with control group that received PBS and monotherapy groups. The average tumor volume in the tumor-bearing mice that received JSI-124 plus 7-acyl lipid A PLGA-NPs combination therapy was found to be significantly lower than that in PBS and monotherapy groups. Our findings show a potential for the combination of STAT3 inhibition in tumor and TLR4 induced DC activation in increasing the efficacy of cancer immunotherapy.

Enhanced immune responses to an adenovirus CEA vaccine in CD4+CD25+ regulatory T-cell inactivated mice

Evaluation of: Elia L, Aurisicchio L, Facciabene A et al. CD4+CD25+ regulatory T-cell inactivation in combination with adenovirus vaccines enhances T-cell responses and protects mice from tumor challenge. Cancer Gene Ther. DOI: 10.1038/sj.cgt.7701004 (2006) (Epub ahead of print).Numerous cancer vaccine clinical trials have been carried out using various antigen-delivery systems and adjuvants. However, the therapeutic outcomes in patients have been minimal. There are numerous reasons for this and one of the current hypotheses is the inhibitory effects of regulatory T cells (Treg) on T-cell effectors. Since most tumor antigens are self antigens, antitumor responses to these antigens are dampened by Treg that are present to prevent autoreactive T cells from damaging healthy tissue. The paper by Elia and colleagues describes an alternative strategy to overcome the suppressive effects of Treg cells and generate enhanced cellular responses.

Glucocorticoid‐induced tumour necrosis factor receptor family‐related receptor signalling exacerbates hapten‐induced colitis by CD4+ T cells

The glucocorticoid-induced tumour necrosis factor receptor family related gene (GITR) has been reported to be expressed on the activated T and CD4(+)CD25(+) regulatory T cells (Treg). Signalling triggered by GITR not only neutralizes the suppressive effect of Treg cells, but also augments activation, proliferation and cytokine production of effector T cells. To test the role of GITR in 2,4,6-trinitrobenzene sulphonic acid (TNBS)-induced colitis - a murine model of mucosal inflammation - TNBS-injected Balb/c mice were treated with agonistic anti-GITR monoclonal antibody (mAb). Anti-GITR treatment increased the death rate compared to rat IgG-treated mice. Typically, death occurred within 4 days after the TNBS injection when the mice were treated with anti-GITR. The mice that survived anti-GITR treatment suffered from severe inflammation in their entire intestines. CD4(+) T-depletion protected the mice from colitis; even an anti-GITR effect was not apparent. In contrast, CD8(+) T depletion showed less protective than did CD4(+) T depletion. Stimulation of GITR enhanced the production of proinflammatory cytokines including interferon (IFN)-gamma, tumour necrosis factor (TNF)-alpha, interleukin (IL)-6 and IL-12. It also enhanced the humoral response such as serum levels of IgG(2b) and IgA, which was completely dependent on CD4(+) T cells. Taken together, this study demonstrated that GITR signalling on CD4(+) T cells is involved in the development and progress of colitis by enhancing both T helper type 1 (Th1) and Th2 type responses.

Signaling triggered by glucocorticoid-induced tumor necrosis factor receptor family-related gene: Regulation at the interface between regulatory T cells and immune effector cells

Mammals and other higher vertebrates have developed an adaptive immune system to defy effectively countless pathogens and cancerous cells encountered during the lifetime of an individual. B and T lymphocytes, which are essential in orchestrating adaptive immune responses, express surface receptors specific for foreign and abnormal self-antigens. Genesis of this antigen receptor repertoire poses significant risks for autoimmunity caused by self-reactive lymphocytes. Therefore, organisms with adaptive immune systems have evolved central and peripheral tolerance mechanisms. In peripheral tissues, regulatory T (Treg) cells function in a dominant, cell-extrinsic manner to limit inflammatory responses and autoimmune disorders. To tap the potential clinical utility of these specialized lymphocytes, advances have been made in understanding how Treg cell-mediated suppression of immune effector cells is achieved and regulated. Importantly, signaling induced by a recently identified member of the tumor necrosis factor receptor (TNFR) family, termed glucocorticoid-induced TNFR family-related gene (GITR), abrogates the suppressive effects of Treg cells. GITR plays a pivotal role in controlling T cell-mediated responses in experimental models of organ-specific autoimmunity, chronic infection, and anti-tumor immunity. These findings highlight the importance of elucidating the molecular underpinnings of GITR-induced signaling. We propose that GITR employs adapter proteins, including TNFR-associated factors (TRAFs), to regulate diverse signaling pathways and transcriptional programs that control the interplay between Treg cells and immune effector cells.