Regulatory T Cells Reversibly Suppress Cytotoxic T Cell Function Independent of Effector Differentiation

Mempel, Thorsten R.; Pittet, Mikaël J.; Khazaie, Khashayarsha; Weninger, Wolfgang; Weissleder, Ralph; Boehmer, Harald von; Andrian, Ulrich H. von

doi:10.1016/j.immuni.2006.04.015

Cited by 453 publications

(492 citation statements)

References 51 publications

Supporting

Mentioning

454

Contrasting

Unclassified

Order By: Relevance

“…We have demonstrated that the local intratumoral depletion of these regulatory T cells changes the cytokine milieu of the tumor, unmasks the immunogenicity of tumor, and reverses CTL tolerization, leading to the rapid rejection of well-established tumors [81]. Our data support the idea that regulatory T cells inhibit not only the early priming events, but also the effector function of T cells inside tumors, which is supported by a recent study [82].…”

Section: The Immunosuppressive Environment Inside Tumorssupporting

confidence: 86%

“…These CD4 + CD25 + regulatory T cells seem not only to inhibit developing tumor-specific CD8 + T cells from gaining full effector function, but can even block transferred, fully activated tumor-specific T cells from mediating tumor rejection in vivo [82]. We have demonstrated that the local intratumoral depletion of these regulatory T cells changes the cytokine milieu of the tumor, unmasks the immunogenicity of tumor, and reverses CTL tolerization, leading to the rapid rejection of well-established tumors [81].…”

Section: The Immunosuppressive Environment Inside Tumorsmentioning

confidence: 99%

See 1 more Smart Citation

Targeting tumors with LIGHT to generate metastasis-clearing immunity

Yü¹,

Fu²

2008

Cytokine & Growth Factor Reviews

View full text Add to dashboard Cite

Metastastic diseases cause the majority of morbidity and mortality of cancer patients. Established tumors form both physical and immunological barriers to limit immune detection and destruction. Current immunotherapy of vaccination and adoptive transfer shows limited effect at least in part due to the existing barriers in the tumors and depending on the knowledge of tumor antigens. Tumor necrosis factor superfamily member 14 (TNFSF14) LIGHT interacts with stromal cells, dendritic cells, NK cells, naïve and activated T cells and tumor cells inside the tumor tissues via its two functional receptors, HVEM and lymphotoxin β receptor (LTβR). Targeting tumor tissues with LIGHT leads to augmentation of priming, recruitment, and retention of effector cells at tumor sites, directly or indirectly, to induce strong anti-tumor immunity to inhibit the growth of primary tumors as well as eradicate metastases. Intratumor treatment would break tumor barriers and allow strong immunity against various tumors without defining tumor antigens. This review summarizes recent findings to support that LIGHT is a promising candidate for an effective cancer immunotherapy.

show abstract

Section: The Immunosuppressive Environment Inside Tumorssupporting

confidence: 86%

Section: The Immunosuppressive Environment Inside Tumorsmentioning

confidence: 99%

Targeting tumors with LIGHT to generate metastasis-clearing immunity

Yü¹,

Fu²

2008

Cytokine & Growth Factor Reviews

View full text Add to dashboard Cite

show abstract

“…On the contrary, granzyme B and perforin were rarely expressed by CD8 þ T cell-derived TILs. Mempel et al 29 reported that the regulatory T cellinduced failure of cytotoxic T lymphocytes (CTLs) to kill target cells in vivo was correlated with impaired release of lytic granules. These results suggested that regulatory …”

Section: Discussionmentioning

confidence: 99%

“…Regulatory T cells are proposed to reversibly suppress cytotoxic T cell function independent of effector differentiation. 29 Regulated CTLs exhibited no defect in proliferation, induction of cytotoxic effector molecules and secretory granules, in situ motility, or ability to form antigen-dependent conjugates with target cells. Only granule exocytosis by CTLs was markedly impaired in the presence of regulatory T cells.…”

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

confidence: 97%

See 1 more Smart Citation

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

Chang

Huang

et al. 2010

Cancer

View full text Add to dashboard Cite

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.

show abstract