Regulatory T-cell Trafficking: From Thymic Development to Tumor-Induced Immune Suppression

Mailloux, Adam W.; Young, Matthew R.

doi:10.1615/critrevimmunol.v30.i5.30

Cited by 84 publications

(59 citation statements)

References 124 publications

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“…In contrast, ATP is released by tumor cells as shown in vivo (6) and in vitro (this article), and ATP stimulatory (T regs )/inhibitory (activated CD4 + cells) activity may represent a tumor-escape mechanism from the immune system. This scenario is consistent with the finding of high numbers of T regs in the cellular milieu of advanced tumors (53,54). The complex interplay between the inflammatory microenvironment, tumor cells, and effector cells of the immune system is currently investigated in our laboratory, in vivo, in animal models.…”

Section: Discussionsupporting

confidence: 85%

Extracellular ATP Exerts Opposite Effects on Activated and Regulatory CD4+ T Cells via Purinergic P2 Receptor Activation

Trabanelli

Očadlíková

Gulinelli

et al. 2012

The Journal of Immunology

113

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It has been reported that ATP inhibits or stimulates lymphoid cell proliferation depending on the cellular subset analyzed. In this study, we show that ATP exerts strikingly opposite effects on anti-CD3/CD28–activated and regulatory CD4+ T cells (Tregs), based on nucleotide concentration. We demonstrate that physiological concentrations of extracellular ATP (1–50 nM) do not affect activated CD4+ T cells and Tregs. Conversely, higher ATP concentrations have a bimodal effect on activated CD4+ T cells. Whereas 250 nM ATP stimulates proliferation, cytokine release, expression of adhesion molecules, and adhesion, 1 mM ATP induces apoptosis and inhibits activated CD4+ T cell functions. The expression analysis and pharmacological profile of purinergic P2 receptors for extracellular nucleotides suggest that activated CD4+ T cells are induced to apoptosis via the upregulation and engagement of P2X7R and P2X4R. On the contrary, 1 mM ATP enhances proliferation, adhesion, migration, via P2Y2R activation, and immunosuppressive ability of Tregs. Similar results were obtained when activated CD4+ T cells and Tregs were exposed to ATP released by necrotized leukemic cells. Taken together, our results show that different concentrations of extracellular ATP modulate CD4+ T cells according to their activated/regulatory status. Because extracellular ATP concentration highly increases in fast-growing tumors or hyperinflamed tissues, the manipulation of purinergic signaling might represent a new therapeutic target to shift the balance between activated CD4+ T cells and Tregs.

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Section: Discussionsupporting

confidence: 85%

Extracellular ATP Exerts Opposite Effects on Activated and Regulatory CD4+ T Cells via Purinergic P2 Receptor Activation

Trabanelli

Očadlíková

Gulinelli

et al. 2012

The Journal of Immunology

113

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“…Previous studies suggested that Tregs accumulate in tumor microenvironment and suppress antitumor immune responses (4,20). In our study, we also observed that Tregs were increased in lung cancers, both in peripheral blood and MPE.…”

Section: Discussionsupporting

confidence: 84%

“…Within the tumor microenvironment, Tregs have been demonstrated to be coopted by tumor cells to escape immune surveillance (4). The increased accumulation of Tregs in tumor is associated with unfavorable prognosis in several kinds of cancers (5).…”

Section: Introductionmentioning

confidence: 99%

miR141–CXCL1–CXCR2 Signaling–Induced Treg Recruitment Regulates Metastases and Survival of Non–Small Cell Lung Cancer

Tang

et al. 2014

Molecular Cancer Therapeutics

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Patients with non-small cell lung cancer (NSCLC) with malignant pleural effusion (MPE) have a short median survival time and increased regulatory T cells (Treg). However, it is unclear whether some specific factors in MPE are involved in Treg recruitment in the progression of NSCLC. Here, we found that Treg population was increased in MPE and inversely correlated with patient survival (P < 0.001). Increased level of CXCL1 in MPE was associated with recruitment of Tregs (P < 0.01). Moreover, miR141 regulated expression of CXCL1 in lung cancer cells, whereas the luciferase test confirmed that CXCL1 is a target of miR141. Chemotaxis assay showed that the miR141-CXCL1-CXCR2 pathway regulates migration of Tregs into MPE. Furthermore, miR141 significantly inhibited tumor growth and metastasis in an immunecompetent mouse model. This suppressive function was mediated by the CXCL1-CXCR2 pathway and recruitment of Tregs. Our study uncovered a causative link between microRNA and development of MPE. Mechanistically, decreased expressions of miR141, associated with the survival of patients with NSCLC with MPE, resulted in the increased production of CXCL1 and recruitment of Tregs to promote immune escape of tumor. Mol Cancer Ther; 13(12); 3152-62. Ó2014 AACR.

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“…However, during the treatment period, the metastatic cancer from RCC spread, mainly to the pancreas and lungs. Generally, an immune cell-inhibiting mechanism is present in the microcirculatory environment of tumors (20). A trace number of cancer cells of RCC were latently present under the control of the immunological surveillance mechanism, but it may have manifested because the DLBCL tumor volume rapidly increased and inhibited immunity, and the subsequent growth of metastatic cancer cells from RCC may have been slightly rapid, unlike the slow growth previously reported (1,6,17).…”

Section: Discussionmentioning

confidence: 93%

Late duodenal metastasis from renal cell carcinoma with newly developed malignant lymphoma: A case report

Saito¹,

Senjo²,

Kanaya³

et al. 2018

mol clin onc

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Abstract. Duodenal metastasis from renal cell carcinoma (RCC) is rare. The current case report presents a very rare case of late duodenal metastasis from RCC with newly developed malignant lymphoma (diffuse large B-cell lymphoma: DLBCL) at the same time. A 64-year-old man with systemic lymph nodes swelling who had undergone left nephrectomy for RCC 25 years previously, was admitted to the present hospital. Inguinal lymph node biopsy was performed, leading to a diagnosis of DLBCL. fluorine-18-fluorodeoxy-glucose ( 18 F-FDG)-positron emission tomography (PET)/computed tomography (CT) revealed multiple lymph nodes, spleen, and ileocecal lesions. CT revealed an obvious hypervascular tumor involving the duodenum/pancreatic head. The tumor was false-negative on 18 F-FDG-PET/CT. On esophagogastroduodenoscopy, the tumor was detected in the descending portion of the duodenum and was observed to be consistent with the submucosal tumor with a central ulcer, resembling those of ulcer-forming DLBCL. A biopsy was then performed carefully, and a clear cell RCC-derived metastatic cancer was diagnosed. Ileocolonoscopy revealed mucosal thickening of the terminal ileum, and led to a diagnosis of DLBCL infiltration with biopsy. To the best of the author's knowledge, this is the first case report of the coexistence of metastatic cancer from RCC and malignant lymphoma in the small intestine simultaneously. It was necessary to make a careful differential diagnosis in the imaging studies.

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Regulatory T-cell Trafficking: From Thymic Development to Tumor-Induced Immune Suppression

Cited by 84 publications

References 124 publications

Extracellular ATP Exerts Opposite Effects on Activated and Regulatory CD4+ T Cells via Purinergic P2 Receptor Activation

Extracellular ATP Exerts Opposite Effects on Activated and Regulatory CD4+ T Cells via Purinergic P2 Receptor Activation

miR141–CXCL1–CXCR2 Signaling–Induced Treg Recruitment Regulates Metastases and Survival of Non–Small Cell Lung Cancer

Late duodenal metastasis from renal cell carcinoma with newly developed malignant lymphoma: A case report

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