Specific Recruitment of CC Chemokine Receptor 4–Positive Regulatory T Cells in Hodgkin Lymphoma Fosters Immune Privilege

Ishida, Takashi; Ishii, Toshihiko; Inagaki, Atsushi; Yano, Hiroki; Komatsu, Hirokazu; Iida, Shinsuke; Inagaki, Hiroshi; Ueda, Ryuzo

doi:10.1158/0008-5472.can-06-0261

Cited by 273 publications

(228 citation statements)

References 32 publications

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“…It has been shown that chemokine receptors CCR3, CCR4, and CCR5 could mediate trafficking of Tregs to tumors (8,(14)(15)(16). We next examined the expression of these chemokine receptors on CD103 + Tregs in the spleen and tumors of mice bearing CT26 tumors.…”

Section: Tregs In Vitromentioning

confidence: 99%

The Indispensable Role of CCR5 for In Vivo Suppressor Function of Tumor-Derived CD103+ Effector/Memory Regulatory T Cells

Chang

Lin

Kang

et al. 2012

The Journal of Immunology

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CD103 is a marker for identification of effector/memory regulatory T cells (Tregs). CD103+ Tregs are potent suppressors of tissue inflammation in several infectious diseases, autoimmune diseases, and cancers. However, the underlying mechanisms for this potent suppression ability remain unclear. The current study was designed to clarify this issue. Unexpectedly, we found both CD103+ and CD103− Tregs had similar suppression capacity in vitro. We then chose a murine tumor model for investigation of the in vivo behavior of these Tregs. The suppression ability in vivo against the anti-tumor ability of CD8+ T cells was restricted to CD103+ Tregs although both Tregs had equal in vitro suppression ability. In addition, CD103+ Tregs expressed significantly higher levels of CCR5 than those of CD103− Tregs and accumulated more in tumors than did CD103− Tregs. Furthermore, blockade of CCR5 signaling, either by CCR5−/−CD103+ Tregs or by CCL5 knockdown tumor, could reduce the migration of CD103+ Tregs into tumors and impair their in vivo suppression ability. In conclusion, these results indicate that the potent in vivo suppression ability of CD103+ Tregs is due to the tissue-migration ability through CCR5 expression.

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Section: Tregs In Vitromentioning

confidence: 99%

The Indispensable Role of CCR5 for In Vivo Suppressor Function of Tumor-Derived CD103+ Effector/Memory Regulatory T Cells

Chang

Lin

Kang

et al. 2012

The Journal of Immunology

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“…7,8 Elevated levels of CCL22 have been described in many human tumors, including B-CLL, Hodgkin lymphoma, breast, lung and gastrointestinal cancers. [9][10][11][12][13][14] For many of these tumors, elevated intratumoral CCL22 concentrations are associated with a higher tumor infiltration by Treg. Treg are an inhibitory subset of T helper cells, whose function is to suppress cytotoxic T effector cell functions, [15][16][17] involving cell-contact dependent and cell-contact independent mechanisms such as consumption of IL-2, expression of the cellsurface antigen CTLA-4 and secretion of inhibitory cytokines such as TGF-b and IL-10.…”

Section: Introductionmentioning

confidence: 99%

Cancer cell-derived IL-1α induces CCL22 and the recruitment of regulatory T cells

et al. 2016

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In cancer patients, immunosuppression through regulatory T cells (Treg) is a crucial component of tumor immune evasion and contributes to disease progression. Tumor-infiltrating Treg in particular suppress local effector T cell responses and are associated with poor prognosis in tumors such as human pancreatic cancer or hepatocellular carcinoma (HCC). The chemokine CCL22 is known to recruit Treg into the tumor tissue and many types of human tumors are known to express high levels of CCL22. The mechanisms leading to intratumoral secretion of CCL22 are so far unknown. We demonstrate here that intratumoral CCL22 is induced in tumor-infiltrating immune cells through cancer cell-derived interleukin-1 (IL-1a). In pancreatic cancer and HCC, CCL22 is produced by intratumoral dendritic cells, while the cancer cells themselves do not secrete CCL22 in vitro and in vivo. Incubation of human peripheral blood mononuclear cells (PBMC) or murine splenocytes with tumor cells or tumor cell supernatants strongly induced CCL22 secretion in vitro. Tumor cell supernatants contained IL-1 and CCL22 induction in PBMC could be specifically prevented by the IL-1 receptor antagonist anakinra or by transfection of tumor cell lines with IL-1 siRNA, leading to a suppression of Treg migration. In conclusion, we identify here tumor cell-derived IL-1a as a major inducer of the Treg attracting chemokine CCL22 in human cancer cells. Therapeutic blockade of the IL-1 pathway could represent a promising strategy to inhibit tumorinduced immunosuppression.

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“…42 MDC/CCL22 and TARC/CCL17 share the receptor CCR4, by which TH 2 and regulatory T cells can be attracted by Hodgkin and Reed-Sternberg cells. 43,44 However, it could recently be shown that the majority of T cells in classical Hodgkin lymphoma microenvironment represents TH 1 cells. 45 In conclusion, three of four genes overexpressed in the Hodgkin and Reed-Sternberg cells in comparison with the tumor cells of ALK À anaplastic large cell lymphoma are also expressed in antigenpresenting cells and are related to the interactions between Hodgkin and Reed-Sternberg cells and surrounding T cells.…”

Section: Discussionmentioning

confidence: 99%

A novel immunohistochemical classifier to distinguish Hodgkin lymphoma from ALK anaplastic large cell lymphoma

et al. 2014

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Classical Hodgkin lymphoma and ALK À anaplastic large cell lymphoma share many features like strong CD30 expression and usually loss of B-and T-cell markers. However, their clinical course is dramatically different with curability rates of 490% for classical Hodgkin lymphoma and an unfavorable prognosis for anaplastic large cell lymphoma. Classical Hodgkin lymphoma and ALK À anaplastic large cell lymphoma can usually be distinguished by PAX5 expression in the Hodgkin and Reed-Sternberg cells of classical Hodgkin lymphoma and expression of cytotoxic molecules in tumor cells of anaplastic large cell lymphoma. However, in some cases the differential diagnosis is difficult owing to absence of established markers. To be able to better classify these cases, we reevaluated gene expression data of microdissected tumor cells of both lymphomas for differentially expressed genes. A classifier was established, comprising four genes strongly expressed in Hodgkin and Reed-Sternberg cells of classical Hodgkin lymphoma (MDC/CCL22, CD83, STAT3, and TUBB2B). Applying this classifier to a test cohort, Hodgkin lymphoma was successfully distinguished from ALK À anaplastic large cell lymphoma with an accuracy of 97% (43/44). MDC/CCL22, CD83, and STAT3 have also been found to be expressed in antigen-presenting cells. Therefore, based on our established classifier, Hodgkin and Reed-Sternberg cells differ from tumor cells of anaplastic large cell lymphoma, which can successfully be applied for practical purposes in histopathologic diagnostics.

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Specific Recruitment of CC Chemokine Receptor 4–Positive Regulatory T Cells in Hodgkin Lymphoma Fosters Immune Privilege

Cited by 273 publications

References 32 publications

The Indispensable Role of CCR5 for In Vivo Suppressor Function of Tumor-Derived CD103+ Effector/Memory Regulatory T Cells

The Indispensable Role of CCR5 for In Vivo Suppressor Function of Tumor-Derived CD103+ Effector/Memory Regulatory T Cells

Cancer cell-derived IL-1α induces CCL22 and the recruitment of regulatory T cells

A novel immunohistochemical classifier to distinguish Hodgkin lymphoma from ALK anaplastic large cell lymphoma

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