Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0178874 (tumor progression)
 40,807 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The peripheral tolerance mechanism prevents effective antitumor immunity, even though tumor cells possess recognizable tumor-associated Ags. Recently, it has been elucidated that regulatory T cells (Treg) play a critical role in maintaining not only self-tolerance, but also tolerance of tumor cells. However, because the Treg that maintain self-tolerance arise naturally in the thymus and are thought to be anergic in peripheral, it is still unclear where and when Treg for tumor cells are generated. In this study we analyze tumor-draining lymph nodes (LNs) and demonstrate that both antitumor effector T cells and Treg capable of abrogating the antitumor reactivity of the effector T cells are primed in the same LNs during tumor progression. The regulatory activity generated in tumor-draining LNs exclusively belonged to the CD4(+) T cell subpopulation that expresses both CD25 and a high level of CD62L. Forkhead/winged helix transcription factor gene expression was detected only in the CD62L(high)CD4(+)CD25(+) T cells. CD62L(high)CD4(+)CD25(+) Treg and CD62L(low)CD4(+)CD25(+) T cells, which possess effector T cell functions, had comparable expression of LFA-1, VLA-4, CTLA-4, lymphocyte activation gene-3, and glucocorticoid-induced TNFR. Thus, only CD62L expression could distinguish regulatory CD4(+)CD25(+) cells from effector CD4(+)CD25(+) cells in draining LNs as a surface marker. The Treg generated in tumor-draining LNs possess the same functional properties as the Treg that arise naturally in the thymus but recognize tumor-associated Ag. CD62L(high)CD4(+)CD25(+) Treg contained a subpopulation that expressed CD86. Blocking experiments revealed that ligation of CTLA-4 on effector T cells by CD86 on Treg plays a pivotal role in regulating CD4(+) effector T cells.
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PMID:Both regulatory T cells and antitumor effector T cells are primed in the same draining lymph nodes during tumor progression. 1621 Jun 9

Suppressor/regulatory T cells were first shown to have an impact on cancer progression in experimental tumor models during the 1970s. However, the lack of specific markers hindered mechanistic investigations, and skepticism grew in the scientific community due to variability in cell populations and reported functions. The identification of regulatory CD4(+)CD25(+) T cells has generated a great deal of renewed interest in cells that have immune regulatory properties. This article will provide a brief historical review of suppressor T cells and cancer, experimental and clinical evidence that CD4(+)CD25(+) natural regulatory T cells play a role in cancer progression, and briefly discuss current strategies to inhibit these cells in an effort to enhance cancer immunotherapy.
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PMID:Suppression of anti-cancer immunity by regulatory T cells: back to the future. 1637 1

Naturally occurring CD25(+)CD4(+) regulatory T cells (T(R) cells), which specifically express the transcription factor Foxp3, engage in the maintenance of immunological self-tolerance and suppressive control of aberrant or excessive immune responses to foreign antigens. They may, on the other hand, impede immune surveillance against cancer and hamper the development of effective immunity to autologous tumor cells. Indeed, natural T(R) cells have been observed to predominantly infiltrate tumor masses especially in the early phase of tumor progression. Depletion of natural T(R) cells by removing CD25(+) T cells prior to tumor challenge is therefore able to provoke effective tumor immunity in animals. Furthermore, attenuation of T(R) cell-mediated suppression in on-going anti-tumor immune responses, for example by altering signaling through CTLA-4 or GITR expressed by natural T(R) cells, can enhance the responses and thereby eradicate advanced cancers. A combination of depletion or attenuation of T(R) cells and concomitant stimulation of effector T cells, systemically or locally in tumors, may be a feasible immunotherapy for cancer.
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PMID:Regulatory T cells in immune surveillance and treatment of cancer. 1637 2

This study was aimed to analyze the proportion of T cell subsets, CD4(+) CD25(high) regulating T cells (Tr) in peripheral blood of B-NHL patients and their change regularity, and to investigate the immunosuppression mechanism and influence of chemotherapy on immunosuppression function of B-NHL patients. The peripheral blood was collected from 42 patients with B-NHL, 36 patients with B-NHL who achieved partial remission (PR) or complete remission (CR) after 4 - 6 cycles of chemotherapy and 15 healthy controls. By using monoclonal antibodies, the blood samples were evaluated with the flow cytometry for lymphocyte subsets and Tr cells. The results showed that the proportion of CD3(+) and CD4(+) T cells, and the ratio of CD4/CD8 in patients with B-NHL group was significantly less than those in the healthy controls, i.e. (68.33 +/- 15.27)% versus (72.06 +/- 9.26)%; (34.47 +/- 12.84)% versus (42.45 +/- 9.2)%; 1.36 +/- 0.26 versus 1.92 +/- 0.20, but the prevalence of the CD4(+) CD25(high) Tr cells was significantly higher than those in the healthy group [(4.10 +/- 1.21)% versus (2.04 +/- 1.03)%, P < 0.001]. The ratio of CD4/CD8 in chemotherapy group was lower than that in control, but the proportion of CD4(+) CD25(high) Treg cells in chemotherapy group was higher than those before chemo-/radio-therapy and the control. It is concluded that the relative increase of CD4(+) CD25(high) Tr cells in peripheral blood of B-NHL patients may be related to immunosuppression and tumor progression.
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PMID:[CD4+ CD25high regulatory T cells in peripheral blood of patients with B cell non-Hodgkin's lymphoma]. 1658 6

Lymphocytopenia is one of the most negative biological prognostic factors in cancer patients. Lymphocytopenia may depend on tumor progression, or on various anticancer therapies. In particular, radiotherapy (RT) may induce direct lymphocyte damage. The present study was carried out to evaluate the influence of pelvic irradiation on lymphocyte number and lymphocyte subpopulations in patients with gynecologic tumors. The study included 40 patients affected by locally limited or advanced uterine tumors, who underwent pelvic irradiation for a total dose of 50.4 Gy. RT induced a significant decline in total lymphocyte number, with values lower than 500/mm3 in 29/40 (73%) patients and with a mean decrease of 71 +/- 4%. In the same way, T lymphocyte, CD4, CD8 and NK cell mean numbers significantly decreased under RT. The decline in NK and CD8 cells was limited to the first 2-3 weeks of irradiation, whereas that involving T lymphocytes and CD4 cells was progressive and persistent until the end of RT. Finally, the decline in total lymphocyte number was significantly greater in patients who had no tumor regression in response to RT. This study confirms that pelvic RT may induce severe lymphocytopenia which could negatively influence the efficacy of RT itself.
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PMID:Radiotherapy-induced lymphocytopenia: changes in total lymphocyte count and in lymphocyte subpopulations under pelvic irradiation in gynecologic neoplasms. 1660 31

CD4(+)CD25(+) regulatory T cells have been characterized as a critical population of immunosuppressive cells. They play a crucial role in cancer progression by inhibiting the effector function of CD4(+) or CD8(+) T lymphocytes. However, whether regulatory T lymphocytes that expand during tumor progression can modulate dendritic cell function is unclear. To address this issue, we have evaluated the inhibitory potential of CD4(+)CD25(+) regulatory T cells from mice bearing a BCR-ABL(+) leukemia on bone marrow-derived dendritic cells. We present data demonstrating that CD4(+)CD25(+)FoxP3(+) regulatory T cells from tumor-bearing animals impede dendritic cell function by down-regulating the activation of the transcription factor NF-kappaB. The expression of the co-stimulatory molecules CD80, CD86 and CD40, the production of TNF-alpha, IL-12, and CCL5/RANTES by the suppressed DC is strongly down-regulated. The suppression mechanism requires TGF-beta and IL-10 and is associated with induction of the Smad signaling pathway and activation of the STAT3 transcription factor.
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PMID:Tumor-derived CD4(+)CD25(+) regulatory T cell suppression of dendritic cell function involves TGF-beta and IL-10. 1661 96

A phase I trial was conducted to evaluate the feasibility, safety, and efficacy of a dendritic cell-based vaccination in patients with metastatic renal cell carcinoma (RCC). Autologous mature dendritic cells derived from peripheral blood monocytes were pulsed with the HLA-A2-binding MUC1 peptides (M1.1 and M1.2). For the activation of CD4(+) T-helper lymphocytes, dendritic cells were further incubated with the PAN-DR-binding peptide PADRE. Dendritic cell vaccinations were done s.c. every 2 weeks for four times and repeated monthly until tumor progression. After five dendritic cell injections, patients additionally received three injections weekly of low-dose interleukin-2 (1 million IE/m(2)). The induction of vaccine-induced T-cell responses was monitored using enzyme-linked immunospot and Cr release assays. Twenty patients were included. The treatment was well tolerated with no severe side effects. In six patients, regression of the metastatic sites was induced after vaccinations with three patients achieving an objective response (one complete response, two partial responses, two mixed responses, and one stable disease). Additional four patients were stable during the treatment for up to 14 months. MUC1 peptide-specific T-cell responses in vivo were detected in the peripheral blood mononuclear cells of the six patients with objective responses. Interestingly, in patients responding to the treatment, T-cell responses to antigens not used for vaccinations, such as adipophilin, telomerase, or oncofetal antigen, could be detected, indicating that epitope spreading might occur. This study shows that MUC1 peptide-pulsed dendritic cells can induce clinical and immunologic responses in patients with metastatic RCC.
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PMID:Immunologic and clinical responses after vaccinations with peptide-pulsed dendritic cells in metastatic renal cancer patients. 1674 Jul 31

Previously, we found that MUC2 mucins could activate monocytes/macrophages through a scavenger receptor leading to cyclooxygenase (COX) 2 induction and overproduction of prostaglandin E2 (PGE2). To investigate the role of mucins in the tumor-bearing state, we compared s.c. tumor formation by using mucin-producing (TA3-Ha) and mucin-non-producing (TA3-St) cloned variants of mouse mammary adenocarcinomas. Expression of COX2 mRNA and protein and production of PGE2 were elevated in peritoneal macrophages stimulated with epiglycanin, which is a mucin-like glycoprotein produced by TA3-Ha cells. S.c. tumor tissues comprising TA3-Ha cells grew much faster than tissues comprising TA3-St cells. COX2 protein and vascular endothelial growth factor in TA3-Ha tumor tissues were elevated compared with the TA3-St tumor tissues. Although similar numbers of macrophages were observed immunochemically in the two types of tumor tissues, COX2 was induced prominently in the infiltrating macrophages in TA3-Ha tumor tissues but only faintly in TA3-St tumor tissues. Furthermore, angiogenesis progressed remarkably in TA3-Ha tumor tissues but only slightly in TA3-St tumor tissues. Epiglycanin-induced overproduction of PGE2 down-regulated interleukin-12 production by macrophages. IFN-gamma-producing CD4 T cells in spleens obtained from TA3-Ha tumor-bearing mice were significantly reduced compared with TA3-St tumor-bearing mice, suggesting that mucins cause PGE2-mediated immune suppression. Actually, the tumor growth of a TA3-Ha cell xenograft was suppressed effectively by oral administration of a COX2 inhibitor but that of a TA3-St cell one was not. These results suggest that mucins play an important role in tumor progression through overproduction of PGE2.
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PMID:Different progression of tumor xenografts between mucin-producing and mucin-non-producing mammary adenocarcinoma-bearing mice. 1677 91

To analyze the possibility that immunological alteration in asbestos-related diseases (ARDs) such as asbestosis (ASB) and malignant mesothelioma (MM) may affect the progression of cancers, a human adult T cell leukemia virus-immortalized T cell line (MT-2Org) was continuously exposed to 10 mug/ml of chrysotile-B (CB), an asbestos. After at least 8 months of exposure, the rate of apoptosis in the cells became very low and the resultant subline was designated MT-2Rst. The MT-2Rst cells were characterized by (i) enhanced expression of bcl-2, with regain of apoptosis-sensitivity by reduction of bcl-2 by siRNA, (ii) excess IL-10 secretion and expression, and (iii) activation of STAT3 that was inhibited by PP2, a specific inhibitor of Src family kinases. These results suggested that the contact between cells and asbestos may affect the human immune system and trigger a cascade of biological events such as activation of Src family kinases, enhancement of IL-10 expression, STAT3 activation and Bcl-2 overexpression. This speculation was partially confirmed by the detection of elevated bcl-2 expression levels in CD4 + peripheral blood T cells from patients with MM compared with those from patients with ASB or healthy donors. Further studies will be required to verify the role of T cells with enhanced bcl-2 expression in tumor progression induced by asbestos exposure.
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PMID:Involvement of IL-10 and Bcl-2 in resistance against an asbestos-induced apoptosis of T cells. 1685 Jan 64

Although numerous immunotherapeutic strategies have been studied in patients with cancer, consistent induction of clinical responses remains a formidable challenge. Cancer vaccines are often successful at generating elevated numbers of tumor-specific T lymphocytes in peripheral blood, however, despite this, tumors usually continue to grow unabated. Recent evidence suggests that endogenous regulatory cells, known to play a major role in the induction of immune tolerance to self and prevention of autoimmunity, as well as suppressive myeloid cells invoked in the tumor-bearing state, may be largely responsible for preventing effective antitumor immune responses. This review will focus on the major regulatory cell subtypes, including CD4(+)CD25(+) T-regulatory cells, type 1 regulatory T cells, natural killer T cells, and immature myeloid cells. Studies in humans and in animal models have shown a role for all of these cells in tumor progression, although the mechanisms by which they act to suppress immunity remain largely undefined. Elucidation of the dominant molecular mechanisms mediating immune suppression in vivo will allow more precise targeting of the relevant regulatory cell populations, as well as the development of novel strategies and clinical reagents that will directly block molecules that induce the suppression of antitumor immunity.
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PMID:Improving antitumor immune responses by circumventing immunoregulatory cells and mechanisms. 1691 64


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