Granzyme B and Perforin Are Important for Regulatory T Cell-Mediated Suppression of Tumor Clearance

Cao, Xuefang; Cai, Sheng F.; Fehniger, Todd A.; Song, Jiling; Collins, Lynne; Piwnica‐Worms, David; Ley, Timothy J.

doi:10.1016/j.immuni.2007.08.014

Cited by 779 publications

(615 citation statements)

References 45 publications

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“…Ex vivo evaluation of in vivo activated NK and T cells also showed that tumor-activated regulatory T cells can cause the death of NK and CD8 þ T cells in a granzyme B-and/or perforin-dependent pattern. 25 The studies described here suggest that regulatory T cells can suppress the ability of CD8 þ T cells to clear tumors. Our data novelly showed that not only is the granzymeperforin pathway important for the function of NK and CD8 þ T cells, but it may reciprocally be used by regulatory T cells to restrain the activity of these cells.…”

Section: Regulatory T Cells In Endometrial Cancer/chang Et Almentioning

confidence: 70%

“…Regulatory T cells derived from the tumor environment could induce natural killer (NK) and CD8 þ T cell death in a granzyme B-and perforin-dependent fashion. 25 Granzyme B and perforin are therefore relevant for regulatory T cell-mediated suppression of tumor clearance in vivo. Grossman et al demonstrated that activated human regulatory T cells can use the perforin-granzyme pathway to kill a variety of autologous immune cells in vitro.…”

Section: Discussionmentioning

confidence: 99%

“…Regulatory T cells may use the perforin-granzyme pathway as a mechanism to suppress the function of immune cells through suppression of NK and CD8 þ T cells that are responsible for clearing these tumors. 25 Moreover, Zhao et al reported that activated murine regulatory T cells can suppress B cell proliferation also in a granzyme B-and perforin-dependent fashion. 27 Gondek et al reported that activated murine regulatory T cells suppressed CD4 þ CD25 þ T effector cells via a granzyme B-dependent mechanism.…”

Section: Discussionmentioning

confidence: 99%

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Clinical significance of regulatory T cells and CD8+ effector populations in patients with human endometrial carcinoma

Chang

Huang

et al. 2010

Cancer

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BACKGROUND: A study was carried out to determine the functional attributes of CD4 þ CD25 þ regulatory T cells in cancer progression by suppressing antitumor immunity. METHODS: Triple-color flow cytometry was used to study the phenotype expression of CD4 þ CD25 þ regulatory T cells and CD8 þ T cells in the peripheral blood lymphocytes (PBLs) and tumor-infiltrating lymphocytes (TILs) of 57 cases of stage I to IV endometrial carcinoma. The expression of T cell subsets was correlated with clinical prognostic parameters. RESULTS: The prevalence of CD4 þ CD25 þ T cells was significantly higher in the TILs than PBLs. The expression of CD4 þ CD25 þ regulatory T cells in cancer milieu correlated with the tumor grade, stage, and myometrium invasion. The expression of FOXP3 and GITR in CD4 þ CD25 þ regulatory T cells was lower in PBLs than TILs. Most tumor-infiltrating CD8 þ T cells were CD28 À CD45RA À CD45RO þ CCR7 À , suggesting good terminal differentiation. Most of them had an activated role with CD69 þ CD103 þ CD152 þ . Functionally, both granzyme B and perforin were scarcely expressed in peripheral regulatory T cells but were highly expressed in peripheral regulatory T cells in the tumor microenvironment. In contrast, CD8 þ cytotoxic T cells derived from PBLs expressed both granzyme B and perforin, and at significantly higher levels than in TILs. Further functional assays demonstrated that Th1 cytokines and cytotoxic molecules can be synchronously up-regulated in CD8 þ cytotoxic T cells. CONCLUSIONS: Regulatory T cells in the tumor microenvironment may abrogate CD8 þ T cell cytotoxicity in a granzyme B-and perforin-dependent conduit. Decreases in both Th1 cytokines and cytotoxic enzymes are relevant for regulatory T cell-mediated restraint of tumor clearance in vivo. Of clinical significance, the expression of regulatory T cells in TILs may mediate T cell immune repression within cancer milieu and thus greatly correlate with cancer progression. Cancer 2010;116:5777-88.

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Section: Regulatory T Cells In Endometrial Cancer/chang Et Almentioning

confidence: 70%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Clinical significance of regulatory T cells and CD8+ effector populations in patients with human endometrial carcinoma

Chang

Huang

et al. 2010

Cancer

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“…67 Interestingly, CD4 þ Foxp3 þ Treg-mediated inactivation of tumor-specific CTLs in the tumor microenvironment has been shown to be contact dependent and reliant on perforin and granzyme B to the extent that mice lacking this granzyme clear transplanted tumor cell lines more efficiently than do wild-type mice. 68 Therefore, in some settings, a tumor may turn the tables on the immune system by using the destructive power of the perforin/granzyme pathway to its advantage. However, more evidence is required before this concept can be fully embraced.…”

Section: The Perforin-granzyme Pathway In Cancer Preventionmentioning

confidence: 99%

Granzymes in cancer and immunity

2010

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“…There are four mechanisms by which T regs suppress responder T cells [20][21][22][23][24]. First, T regs secrete inhibitory cytokines such as interleukin (IL)-35, IL-10 and transforming growth factor (TGF)-b to inhibit T cells directly.…”

Section: Introductionmentioning

confidence: 99%

Ovarian cancer stem cells promote tumour immune privilege and invasion via CCL5 and regulatory T cells

You

et al. 2017

Clinical and Experimental Immunology

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SummaryEmerging evidence indicates a link between the increased proportion of regulatory T cells (T regs ) and reduced survival in patients who have been diagnosed with cancer. Cancer stem cells (CSCs) have been indicated to play a vital role in tumour initiation, drug resistance and recurrence. However, the relationship between T regs and CSCs remains largely unknown. Here, we sorted out ovarian cancer stem-like side population (SP) cells and CD133 1 cells to investigate the influence of ovarian CSCs on T regs . Among the various immune-related molecules that we assessed, C-C motif chemokine ligand 5 (CCL5) was the most elevated in ovarian CSCs relative to that in the non-CSCs. The expression of its receptor, C-C motif chemokine receptor 5 (CCR5), was also increased on the surface of T regs in ovarian cancer patients. This receptor-ligand expression profile indicated that ovarian CSCs recruit T regs via CCL5-CCR5 interactions. We further assessed the expression of interleukin (IL)-10 in T regs cultured with different cancer cells. For the first time, to our knowledge, our findings describe the relationship between ovarian CSCs and T regs , and demonstrated that these two cell populations co-operate to promote tumour immune tolerance and enhance tumour progression.

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Granzyme B and Perforin Are Important for Regulatory T Cell-Mediated Suppression of Tumor Clearance

Cited by 779 publications

References 45 publications

Clinical significance of regulatory T cells and CD8+ effector populations in patients with human endometrial carcinoma

Clinical significance of regulatory T cells and CD8+ effector populations in patients with human endometrial carcinoma

Granzymes in cancer and immunity

Ovarian cancer stem cells promote tumour immune privilege and invasion via CCL5 and regulatory T cells

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