Inhibit T-cell Function Research Articles

Tumor Secretion of VEGF Induces Endothelial Cells to Suppress T cell Functions Through the Production of PGE2

Endothelial cells are potent regulators of immune cell functions and have therefore been examined to determine their role in tumor-induced immune suppression. Previous studies by our laboratory showed that exposure to Lewis lung carcinoma (LLC)-secreted products induced endothelial cells to suppress T-cell functions in vitro. The current studies examined in vitro and in vivo the mechanism by which tumors induce the formation of suppressor endothelial cells and the means by which suppressor endothelial cells disrupt T-cell functions. In vitro studies demonstrated that inhibition of tumor-derived VEGF with neutralizing antibodies or treatment of endothelial cells with the VEGF receptor tyrosine kinase inhibitor, SU5416, prevented endothelial cells from being induced to suppress T-cell functions. Treatment of tumor-bearing mice with SU5416 blocked the development of endothelial cells that are suppressive to CD4 and CD8 T-cell functions. We next examined the role of suppressor endothelial cell-derived PGE2 in the inhibition of T-cell functions. Abrogation of endothelial cell PGE2 production in vitro with indomethacin prevented tumor-conditioned media from stimulating endothelial cell production of immune inhibitory activity toward T-cell functions. Similar treatment of endothelial cells from lungs of tumor-bearing mice blocked their capacity to produce T-cell-inhibitory mediators. These studies demonstrate that tumor-derived VEGF induces endothelial cells to upregulate production of PGE2 which, in turn, leads to suppression of T-cell functions.

Progress in understanding the human immune responses to Mycobacterium tuberculosis

Development of an effective vaccine against tuberculosis hinges on an improved understanding of the human immune response to Mycobacterium tuberculosis. Work in this area at the University of Texas Health Science Center at Tyler has led to advances in four areas: (1) natural killer cells contribute to innate immunity by lysing M. tuberculosis-infected mononuclear phagocytes, and to adaptive immunity by enhancing the CD8+ T-cell effector function and inhibiting expansion of T regulatory cells; (2) Interferon-gamma plays a central role in resistance to many intracellular pathogens, including M. tuberculosis, and we have identified three transcription factors that bind to the Interferon-gamma proximal promoter and increase Interferon-gamma transcription in live T-cells that are activated by M. tuberculosis antigens; (3) A DNA vaccine that encodes the M. tuberculosis 10fts;kDa culture filtrate protein and the lysosomal integral membrane protein-2 was produced to direct vaccine antigens to the MHC class II processing and presentation pathway. When this vaccine was coated with polyethylenimine and administered to mice, it yielded a remarkably potent pulmonary immune response that reduced the bacillary burden by 90% after M. tuberculosis challenge; (4) The early secreted antigenic target of 6fts;kDa (ESAT-6) is a putative vaccine antigen. We found that high concentrations of this antigen markedly inhibit Interferon-gamma production by T-cells and are working to understand the molecular mechanisms underlying this effect. Developing methods to enhance NK cell functions that favor protective immunity, increase interferon-gamma transcription, elicit protective pulmonary immune responses and prevent ESAT-6 from inhibiting T-cell function will contribute significantly to development of antituberculosis vaccines.

Tumor-Expressed B7-H1 and B7-DC in Relation to PD-1+ T-Cell Infiltration and Survival of Patients with Cervical Carcinoma

The interaction between programmed cell death 1 (PD-1), expressed by activated effector or regulatory T cells, and B7-H1 (PD-L1) and B7-DC (PD-L2) results in the inhibition of T-cell function. The aim of this study was to determine B7-H1, B7-DC, and PD-1 expression in cervical carcinoma. A tissue microarray of a well-defined group of 115 patients was stained with antibodies against B7-H1 and B7-DC. Three-color fluorescent immunohistochemistry was used to study the number and phenotype of tumor-infiltrating T cells expressing PD-1. Additional analyses consisted of in vitro T-cell suppression assays. B7-H1 was expressed in 19%, and B7-DC was expressed by 29% of the 115 tumors. PD-1 was expressed by more than half of both the infiltrating CD8+ T cells and CD4+Foxp3+ T cells, irrespective of B7-H1 or B7-DC expression by tumors. The expression of B7-H1 did not show a direct impact on patient survival. However, subgroup analysis revealed that patients with a relative excess of infiltrating regulatory T cells displayed a better survival when the tumor was B7-H1 positive (P = 0.033). Additional studies showed that the presence of B7-H1 during the activation of CD4+Foxp3+ regulatory T cells impaired their suppressive function in a functional in vitro assay. B7-H1 is expressed on only a minority of cervical cancers and does not influence the survival of patients with cervical cancer. PD-1 is expressed by a vast number of infiltrating CD8 T cells, suggesting that blocking of PD-1 could have therapeutic potential in cervical cancer patients.

Immune System Modulation in Patients with Malignant and Benign Breast Disorders: Tryptophan Degradation and Serum Neopterin

Tryptophan degradation metabolites are known to suppress T-cell function, which is a mechanism of resistance of tumor cells against immune surveillance. The aim of this study was to evaluate tryptophan degradation along with serum neopterin levels in benign and malignant breast disease. Serum tryptophan and kynurenine levels and neopterin concentrations of 30 patients with malignant and 27 patients with benign breast disease were determined by HPLC and ELISA, respectively. The slight increase in tryptophan degradation in a subgroup of cancer patients with higher grade tumors was not statistically significant, but the increased degradation was correlated with higher neopterin concentrations. Neopterin levels in patients with malignant breast disease were significantly higher than in the benign group (p<0.05). Tryptophan degradation positively correlates with the aggressiveness of the tumor because it changes with tumor grade rather than disease stage.

In situ stimulation of CD40 and Toll-like receptor 3 transforms ovarian cancer-infiltrating dendritic cells from immunosuppressive to immunostimulatory cells.

Boosting therapeutically relevant immunity against lethal epithelial tumors may require targeting tumor-induced immunosuppression on an individualized basis. Here, we show that, in the ovarian carcinoma microenvironment, CD11c(+)MHC-II(+) dendritic cells spontaneously engulf tumor materials but, rather than enhancing antitumor immunity, suppress T-cell function. In situ costimulation of CD40 and Toll-like receptor (TLR) 3 on tumor-infiltrating dendritic cells decreased their L-arginase activity, enhanced their production of type I IFN and interleukin-12 (p70), augmented their capacity to process antigens, and up-regulated costimulatory molecules in vivo in mice and in vitro in human dissociated tumors. Synergistic CD40/TLR activation also induced the migration of activated dendritic cells to lymphatic locations and promoted their capacity to present antigens. Correspondingly, without exogenous antigen, combined CD40/TLR agonists boosted measurable T-cell-mediated antitumor immunity and induced the rejection of otherwise lethal i.p. ovarian carcinomas. Our results highlight the potential of transforming tumor-infiltrating dendritic cells (the most abundant leukocyte subset in the solid ovarian carcinoma microenvironment) from an immunosuppressive to an immunostimulatory cell type. Combined administration of synergistic CD40 and TLR3 agonists could enhance their individual therapeutic effects against ovarian and other lethal epithelial cancers.

Opa+and Opa−Isolates ofNeisseria meningitidisandNeisseria gonorrhoeaeInduce Sustained Proliferative Responses in Human CD4+T Cells

T cells may interact with a number of bacterial surface antigens, an encounter which has the potential to downmodulate host immune responses. Neisseria meningitidis, a human colonizer and an agent of septicemia and meningitis, expresses Opa proteins which interact with the CEACAM1 receptor expressed on activated T cells. Since CEACAM1 can act as an inhibitory receptor and T cells in subepithelial tissues may encounter whole bacteria, which often express Opa proteins in vivo, this study assessed primarily if Opa proteins expressed on meningococci affect T-cell functions. In addition, Opa-containing outer membrane vesicles (OMV) have been used as vaccine antigens, and therefore Opa+ and Opa- OMV were also studied. While Opa+ bacteria adhered to CEACAM-expressing T cells, both the Opa+ and Opa- phenotypes induced no to a small transient depression, followed by a prolonged increase in proliferation as well as cytokine production. Such responses were also observed with heat-killed bacteria or OMV. In addition, while anti-CEACAM antibodies alone inhibited proliferation, on coincubation of T cells with bacteria and the antibodies, bacterial effects predominated and were Opa independent. Thus, while Opa proteins of N. meningitidis can bind to T-cell-expressed CEACAM1, this is not sufficient to overcome the T-cell recognition of bacterial factors, which results in a proliferative and cytokine response, an observation consistent with the ability of the host to establish lasting immunity to Opa-expressing meningococci that it frequently encounters. The data also imply that Opa-proficient vaccine preparations may not necessarily inhibit T-cell functions via CEACAM1 binding.

T-cell regulation of neutrophil infiltrate at the early stages of a murine colitis model

T-cells are a main target for antiinflammatory drugs in inflammatory bowel disease. As the innate immune system is also implicated in the pathogenesis of these diseases, T-cell suppressors may not only inhibit T-cell-dependent production of proinflammatory mediators but also affect innate immune cell function. Specifically, these drugs may impair innate immune cell recruitment and activation through inhibition of T-cells or act independent of T-cell modulation. We explored the extent of immune modulation by the T-cell inhibitor tacrolimus in a murine colitis model. We assessed the effects of tacrolimus on trinitro-benzene sulphonic acid (TNBS) colitis in wildtype and Rag2-deficient mice. The severity of colitis was assessed by means of histological scores and weight loss. We further characterized the inflammation using immunohistochemistry and by analysis of isolated intestinal leukocytes at various stages of disease. Tacrolimus-treated wildtype mice were less sensitive to colitis and had fewer activated T-cells. Inhibition of T-cell function was associated with strongly diminished recruitment of infiltrating neutrophils in the colon at the early stages of this model. In agreement, immunohistochemistry demonstrated that tacrolimus inhibited production of the neutrophil chemoattractants CXCL1 and CXCL2. Rag2-deficient mice displayed an enhanced baseline level of lamina propria neutrophils that was moderately increased in TNBS colitis and remained unaffected by tacrolimus. Both the innate and the adaptive mucosal immune system contribute to TNBS colitis. Tacrolimus suppresses colitis directly through inhibition of T-cell activation and by suppression of T-cell-mediated recruitment of neutrophils.

IDO inhibits T-cell function through suppressing Vav1 expression and activation

Purpose: Indoleamine 2,3-dioxygenase (IDO), a tryptophan catabolic enzyme, plays an important role in immune escape through suppressing T-cell function. Since Vav1 signaling pathway regulates T cell homeostasis, this study was designed to test the hypothesis that IDO induces T-cell immunosuppression through inhibiting Vav1 signaling.Results: We found that IDO produced by IDO stably expressing CHO cells significantly inhibited interleukin (IL)-2 expression and proliferative response in T cells and increased apoptosis of T cells. IDO suppressed Vav1 mRNA and protein production in T cells. Furthermore, IDO inhibited TCR activation-induced Vav1 phosphorylation, which represents Vav1’s activation state in T cells. These effects on T-cells induced by co-culture of CHO/IDO with T cells were attenuated by 1-MT.Materials and methods: Chinese hamster ovary (CHO) cells were stably transfected with human IDO (CHO/IDO). CD3+ T cells were isolated from human peripheral blood monouclear cells. After co-culture of CHO/IDO cells with T cells in the presence or absence of an anti-CD3 antibody to activate T cell receptor (TCR) and/or 1-methyl-L-tryptophan (1-MT) to inhibit IDO activity, T cell proliferation and apoptosis were determined. T cell total RNA and cellular protein samples were isolated for detecting Vav1 gene and protein expression and activation state.Conclusions: The inhibitory effects of IDO on T cell immune responses may be through downregulation of Vav1 protein expression and activation. These studies provide insight into understanding the mechanisms of immune escape induced by IDO and therapeutic application of IDO inhibitors for cancer treatment.

Intravenous immunoglobulin G-mediated inhibition of T-cell proliferation reflects an endogenous mechanism by which IgG modulates T-cell activation

Commercial intravenous immunoglobulin G (IVIG) at high doses has therapeutic benefit in autoimmune and inflammatory diseases. It has been shown to inhibit T-cell function but the mechanisms are unclear. Inhibition could result from IVIG processing, donor pooling or intrinsic downregulatory activity of IgG. To address these points, we compared the effects on T-cell activation of IVIG, Fab(2) fragment and IgG isolated from single-donor plasma. We also investigated the role of accessory cells in the IVIG effects using highly purified T cells stimulated through CD3 and CD28 engagement. T-cell proliferation was evaluated by Oregon Green 488 dye dilution and (3)H-thymidine incorporation. IVIG, Fab(2) fragment of IVIG and autologous, single-donor IgG significantly inhibited T-cell proliferation (35-50%), even in the absence of accessory cells. Depletion of IgG from plasma used for culture significantly increased (by 50%) the T-cell proliferation. The addition of physiological concentrations of single-donor, autologous IgG or IVIG to IgG-depleted plasma reduced T-cell proliferation to levels observed in normal plasma. Therefore, donor pooling in IVIG and accessory cells are not required for inhibition of T-cell proliferation by IVIG and the Fab(2) region is sufficient to mediate this inhibition. Suppression of T-cell activation by IVIG likely reflects a physiologic, endogenous mechanism of IgG-mediated regulation of T-cell activation.

Negative regulators of T‐cell activation: potential targets for therapeutic intervention in cancer, autoimmune disease, and persistent infections

The generation of productive adaptive immune responses depends on the antigen-specific activation of T and B cells. The outcome of T-cell receptor engagement is influenced by signals from both positive and negative regulatory molecules that can either activate or inhibit T-cell function. CD28 and cytotoxic T-lymphocyte antigen-4 are the prototypical members of an immunoglobulin domain-containing protein family that play important roles in the control of T-cell responses against infection, cancer, and in autoimmune disease. Although the precise molecular details of their functions are still under active investigation, tumors and chronic pathogens seem to have exploited these pathways to achieve immune evasion. Furthermore, malfunction of the inhibitory arm of the immune response appears responsible for the development of multiple autoimmune pathologies. As a result, the negative regulators of T-cell activation have become attractive targets for therapeutic intervention in cancer, chronic infection, and autoimmune disease. The application of findings from basic research has provided insight into the manipulation of these pathways in the clinic and offers promising strategies for the treatment of disease.

Activated CD11b+CD15+Granulocytes Increase in the Blood of Patients with Uveal Melanoma

To determine whether activated CD11b(+) CD15(+) granulocytes increase in the blood of patients with uveal melanoma. Peripheral blood mononuclear cells (PBMCs) were isolated by density gradient centrifugation from the blood of patients with primary choroidal/ciliochoroidal uveal melanomas (six women, four men; age range, 46-91 years) and healthy control donors (14 women, 10 men; age range, 50-81 years). The expression of CD15 and CD68 on CD11b(+) myeloid cells within PBMCs and primary uveal melanomas was evaluated by flow cytometry. CD3zeta chain expression by CD3epsilon(+) T cells in PBMCs and within primary uveal melanomas was measured as an indirect indication of T-cell function. The percentage of CD11b(+) cells in PBMCs of patients with uveal melanoma increased 1.8-fold in comparison to healthy donors and comprised three subsets: CD68 negative CD15(+) granulocytes, which increased 4.1-fold; CD68(-) CD15(-) cells, which increased threefold; and CD68(+) CD15(low) cells, which were unchanged. A significant (2.7-fold) reduction in CD3zeta chain expression on CD3epsilon(+) T cells, a marker of T-cell dysfunction, was observed in PBMCs of patients with uveal melanoma in comparison with healthy control subjects and correlated significantly with the percentage of CD11b(+) cells in PBMCs. CD3zeta chain expression on T cells within primary tumors was equivalent to CD3zeta expression in PBMCs of the same patient in four of five patients analyzed. Activated CD11b(+) CD15(+) granulocytes expand in the blood of patients with uveal melanoma and may contribute to immune evasion by ocular tumors by inhibiting T-cell function via decreasing CD3zeta chain expression.

Lack of Evidence for Activation of the Hedgehog Pathway in Psoriasis

Recent reports have suggested that the hedgehog (Hh) pathway is activated in lesional psoriatic skin, and that treatment with the Hh pathway antagonist cyclopamine may lead to rapid resolution of the disease. To assess Hh pathway activity in psoriasis, we isolated RNA from lesional and uninvolved skin of 58 psoriatic patients, and from 63 normal control subjects, and subjected these samples to global gene expression profiling on Affymetrix HU133 Plus 2.0 gene arrays. We were especially interested in Hh target genes (PTCH1 and GLI1), whose expression is elevated in response to Hh signaling. The microarray data demonstrated downregulation of PTCH1 expression in uninvolved and lesional skin (1.1-fold and 2-fold, respectively; P<0.0001). Additionally GLI1 mRNA was downregulated in lesional skin (1.7 fold; P<0.05). No significant changes were observed between lesional and uninvolved skin for the Hh ligands or Smoothened. Quantitative PCR confirmed these findings. In situ hybridization for GLI1 and PTCH1 was positive in basal cell carcinoma tumor cells, but was negligible in uninvolved or lesional psoriatic skin. The absence of elevated Hh target gene expression in lesional psoriatic skin indicates that the Hh pathway is not activated in this disease, raising questions regarding the proposed use of Hh antagonists as antipsoriatic agents.

Arginase I–Producing Myeloid-Derived Suppressor Cells in Renal Cell Carcinoma Are a Subpopulation of Activated Granulocytes

Myeloid-derived suppressor cells (MDSC) producing arginase I are increased in the peripheral blood of patients with renal cell carcinoma (RCC). MDSC inhibit T-cell function by reducing the availability of L-arginine and are therefore considered an important tumor escape mechanism. We aimed to determine the origin of arginase I-producing MDSC in RCC patients and to identify the mechanisms used to deplete extracellular L-arginine. The results show that human MDSC are a subpopulation of activated polymorphonuclear (PMN) cells expressing high levels of CD66b, CD11b, and VEGFR1 and low levels of CD62L and CD16. In contrast to murine MDSC, human MDSC do not deplete L-arginine by increasing its uptake but instead release arginase I into the circulation. Activation of normal PMN induces phenotypic and functional changes similar to MDSC and also promotes the release of arginase I from intracellular granules. Interestingly, although activation of normal PMN usually ends with apoptosis, MDSC showed no increase in apoptosis compared with autologous PMN or PMN obtained from normal controls. High levels of VEGF have been shown to increase suppressor immature myeloid dendritic cells in cancer patients. Treatment of RCC patients with anti-VEGF antibody bevacizumab, however, did not reduce the accumulation of MDSC in peripheral blood. In contrast, the addition of interleukin-2 to the treatment increased the number of MDSC in peripheral blood and the plasma levels of arginase I. These results may provide new insights on the mechanisms of tumor-induced anergy/tolerance and may help explain why some immunotherapies fail to induce an antitumor response.

Inhibition of T-cell-Dependent Antibody Production by Quercetin in Mice

The immunosuppressive properties of flavonoids were examined for the first time by testing their effects on T-cell-mediated antibody production, using a classical plague-forming cell (PFC) assay in mice. Among the tested flavonoids including naringenin, chrysin, flavonol, galangin, quercetin, morin, myricetin and biochanin A, only quercetin, orally administered at 25 mg/kg, significantly inhibited the number of IgMproducing PFCs induced by sheep red blood cells (SRBC). Interestingly, biochanin A (isoflavone) increased the number of PFCs, suggesting an immunostimulatory effect. The other flavonoids tested did not inhibit or enhance PFC response significantly. Quercetin was also found to show thymus atrophy dose-dependently at 5-500 mg/kg. All these results indicate that quercetin inhibits in vivo antibody production probably by inhibiting T-cell function.

Secretion of vascular endothelial growth factor by oral squamous cell carcinoma cells skews endothelial cells to suppress T-cell functions

Patients with oral squamous cell carcinoma (OSCC) have severe defects in antitumor immune function. Endothelial cells are potential regulators of immune cell function and have therefore been examined to determine their role in tumor-induced immune suppression. The present studies demonstrated that supernatants from endothelial cells exposed to OSCC-conditioned media (endo OSCC-sup) exhibited elevated levels of the immune suppressive products prostaglandin E 2 (PGE 2) and vascular endothelial growth factor (VEGF) compared with supernatants from endothelial cells treated with medium alone (endo medium) or with keratinocyte-conditioned medium (endo ker-sup). Antibody neutralization of OSCC-derived VEGF prevented tumor-conditioned media from inducing endothelial cells to increase production of PGE 2and VEGF. Furthermore, treatment of T-cells with supernatants from endo OSCC-sup resulted in diminished T-cell proliferation and decreased interferon-γ (IFN-γ) production compared with T-cells treated with medium or supernatants from endo medium or endo ker-sup controls. T-cell levels of granzyme B and perforin were reduced after treatment with supernatant from endo OSCC-sup compared with control treatments. The addition of VEGF neutralizing antibody to the OSCC-conditioned medium prevented endothelial cells from being skewed to downregulate T-cell proliferation and production of IFN-γ, perforin, and granzyme B. Taken together, these studies provide support for the use of VEGF-targeting therapies as an immunotherapeutic agent to block induction of immune suppressive endothelial cells in patients with OSCC.

Intralesional Regulatory T-Cell Suppressive Function during Human Acute and Chronic Cutaneous Leishmaniasis Due to Leishmania guyanensis

The levels of regulatory T cells (Treg cells), analyzed by Foxp3 mRNA expression, were determined in lesions from patients with acute cutaneous leishmaniasis (ACL) and chronic cutaneous leishmaniasis (CCL). We demonstrated that Treg cells preferentially accumulate in lesions from ACL patients during the early phase of infection (lesion duration of less than 1 month). In addition, levels of Foxp3 mRNA transcripts were significantly higher in specimens from patients with CCL than in those from patients with ACL, suggesting a critical role of intralesional Treg cells in CCL. Intralesional Treg cells from both ACL and CCL patients were shown to have suppressive functions in vitro, since they inhibited the gamma interferon (IFN-gamma) produced by CD4(+) CD25(-) T cells purified from peripheral blood mononuclear cells from the same patient in response to Leishmania guyanensis stimulation. Intralesional 2,3-indoleamine dioxygenase (IDO) mRNA expression was associated with that of Foxp3, suggesting a role for IDO in the suppressive activity of intralesional Treg cells. In addition, a role, albeit minor, of interleukin-10 (IL-10) was also demonstrated, since neutralization of IL-10 produced by intralesional T cells increased IFN-gamma production by effector cells in an in vitro suppressive assay. These results confirm the role of intralesional Treg cells in the immunopathogenesis of human Leishmania infection, particularly in CCL patients.

Immune system modulation in patients with malignant and benign breast disorders: tryptophan degradation and serum neopterin

Tryptophan degradation metabolites are known to suppress T-cell function, which is a mechanism of resistance of tumor cells against immune surveillance. The aim of this study was to evaluate tryptophan degradation along with serum neopterin levels in benign and malignant breast disease. Serum tryptophan and kynurenine levels and neopterin concentrations of 30 patients with malignant and 27 patients with benign breast disease were determined by HPLC and ELISA, respectively. The slight increase in tryptophan degradation in a subgroup of cancer patients with higher grade tumors was not statistically significant, but the increased degradation was correlated with higher neopterin concentrations. Neopterin levels in patients with malignant breast disease were significantly higher than in the benign group (p<0.05). Tryptophan degradation positively correlates with the aggressiveness of the tumor because it changes with tumor grade rather than disease stage.

Effect of arginase II on L-arginine depletion and cell growth in murine cell lines of renal cell carcinoma

BackgroundL-arginine is the common substrate for the two isoforms of arginase. Arginase I, highly expressed in the liver and arginase II mainly expressed in the kidney. Arginase I-producing myeloid derived suppressor cells have been shown to inhibit T-cell function by the depletion of L-arginine. On the other hand, arginase II has been detected in patients with cancer and is thought to metabolize L-arginine to L-ornithine needed to sustain rapid tumor growth; however its role in L-arginine depletion is unclear. Thus, in tumor biology, L-arginine metabolism may play a dual role in tumor growth and in the induction of T cell dysfunction. Therefore, we studied in murine renal cell carcinoma (RCC) cell lines, the effect of arginase II on tumor cell proliferation and L-arginine depletion. The effect of arginase inhibitors on cell proliferation was also tested.MethodsThree murine renal cell carcinoma (mRCC) cell lines were tested for the presence of arginase. nor-NOHA, an arginase inhibitor was used to substantiate the effect of arginase on cell growth and L-arginine depletion. Amino acid levels were tested by HPLC.ResultsOur results show that mRCC cell lines express only arginase II and were able to deplete L-arginine from the medium. Cell growth was independent of the amount of arginase activity expressed by the cells. nor-NOHA significantly (P = 0.01) reduced arginase II activity and suppressed cell growth in cells exhibiting high arginase activity.The depletion of L-arginine by mRCC induced the decrease expression of CD3ζ a key element for T-cell function.ConclusionThe results of this study show for the first time that arginase II produced by RCC cell lines depletes L-arginine resulting in decreased expression of CD3ζ. These results indicate that RCC cell lines expressing arginase II can modulate the L-arginine metabolic pathway to regulate both cell growth and T-cell function. Blocking arginase may lead to a decrease in RCC cell growth and aid in restoring immune function by increasing L-arginine availability for T-cell use. Understanding the interplay between arginase II and its interaction with the immune system may provide future therapeutic benefits to treat patients with RCC.

Neurotransmitters activate T-cells and elicit crucial functions via neurotransmitter receptors

Neurotransmitters are traditionally viewed as nerve-secreted molecules that trigger or inhibit neuronal functions. Yet, neurotransmitters bind also their neurotransmitter receptors in T-cells and directly activate or suppress T-cell functions. This review focuses only on the activating effects of neurotransmitters on T-cells, primarily naïve/resting cells, and covers dopamine, glutamate, serotonin, and few neuropeptides: GnRH-I, GnRH-II, substance P, somatostatin, CGRP, and neuropeptide Y. T-cells express many neurotransmitter receptors. These are regulated by TCR-activation, cytokines, or the neurotransmitters themselves, and are upregulated/downregulated in some human diseases. The context - whether the T-cells are naïve/resting or antigen/mitogen/cytokine-activated, the T-cell subset (CD4/CD8/Th1/Th2/Teff/Treg), neurotransmitter dose (low/optimal or high/excess), exact neurotransmitter receptors expressed, and the cytokine milieu - is crucial, and can determine either activation or suppression of T-cells by the same neurotransmitter. T-cells also produce many neurotransmitters. In summary, neurotransmitters activate vital T-cell functions in a direct, potent and specific manner, and may serve for communicating between the brain and the immune system to elicit an effective and orchestrated immune function, and for new therapeutic avenues, to improve T-cell eradication of cancer and infectious organisms.

CTLA-4: Negative Regulator of the Immune Response and a Target for Cancer Therapy

A novel approach for cancer immunotherapy is to augment T-cell-mediated immunity by blocking inhibitory signals that suppress T-cell function. Cytotoxic T-lymphocyte antigen-4 (CTLA-4) is a key negative regulator of T-cell activation. CTLA-4 blockade using anti-CTLA-4 monoclonal antibodies (mAbs) potentiates the T-cell response against tumors, and preliminary data on these agents demonstrate good efficacy and tolerability in the treatment of patients with metastatic melanoma and other cancers. This paper will review data from studies with anti-CTLA-4 mAbs to date, discuss some of the key clinical considerations emerging from early clinical trials with this therapeutic strategy, and provide an overview of ongoing and planned clinical trials for anti-CTLA-4 mAb therapy in metastatic melanoma and other cancers.