Regulatory T cells (Tregs) are critical for maintaining immune homeostasis, but their presence in tumor tissues impairs anti-tumor immunity and portends poor prognoses in cancer patients. Here, we reveal a mechanism to selectively target and reprogram the function of tumor-infiltrating Tregs (TI-Tregs) by exploiting their dependency on the histone H3K27 methyltransferase enhancer of zeste homolog 2 (EZH2) in tumors. Disruption of EZH2 activity in Tregs, either pharmacologically or genetically, drove the acquisition of pro-inflammatory functions in TI-Tregs, remodeling the tumor microenvironment and enhancing the recruitment and function of CD8+ and CD4+ effector T cells that eliminate tumors. Moreover, abolishing EZH2 function in Tregs was mechanistically distinct from, more potent than, and less toxic than a generalized Treg depletion approach. This study reveals a strategy to target Tregs in cancer that mitigates autoimmunity by reprogramming their function in tumors to enhance anti-cancer immunity.

Targeting EZH2 Reprograms Intratumoral Regulatory T Cells to Enhance Cancer Immunity / D. Wang, J. Quiros, K. Mahuron, C.C. Pai, V. Ranzani, A. Young, S. Silveria, T. Harwin, A. Abnousian, M. Pagani, M.D. Rosenblum, F. Van Gool, L. Fong, J.A. Bluestone, M. Dupage. - In: CELL REPORTS. - ISSN 2211-1247. - 23:11(2018 Jun), pp. 3262-3274.

Targeting EZH2 Reprograms Intratumoral Regulatory T Cells to Enhance Cancer Immunity

V. Ranzani;M. Pagani;
2018

Abstract

Regulatory T cells (Tregs) are critical for maintaining immune homeostasis, but their presence in tumor tissues impairs anti-tumor immunity and portends poor prognoses in cancer patients. Here, we reveal a mechanism to selectively target and reprogram the function of tumor-infiltrating Tregs (TI-Tregs) by exploiting their dependency on the histone H3K27 methyltransferase enhancer of zeste homolog 2 (EZH2) in tumors. Disruption of EZH2 activity in Tregs, either pharmacologically or genetically, drove the acquisition of pro-inflammatory functions in TI-Tregs, remodeling the tumor microenvironment and enhancing the recruitment and function of CD8+ and CD4+ effector T cells that eliminate tumors. Moreover, abolishing EZH2 function in Tregs was mechanistically distinct from, more potent than, and less toxic than a generalized Treg depletion approach. This study reveals a strategy to target Tregs in cancer that mitigates autoimmunity by reprogramming their function in tumors to enhance anti-cancer immunity.
English
Animals; CD4-Positive T-Lymphocytes; CD8-Positive T-Lymphocytes; Cell Line, Tumor; Enhancer of Zeste Homolog 2 Protein; Forkhead Transcription Factors; Humans; Interferon-gamma; Lymphocytes, Tumor-Infiltrating; Mice; Mice, Inbred C57BL; Mice, Knockout; Neoplasms; T-Lymphocytes, Regulatory; Tumor Microenvironment; Tumor Necrosis Factor-alpha
Settore BIO/11 - Biologia Molecolare
Articolo
Esperti anonimi
Pubblicazione scientifica
giu-2018
Elsevier
23
11
3262
3274
13
Pubblicato
Periodico con rilevanza internazionale
scopus
Aderisco
info:eu-repo/semantics/article
Targeting EZH2 Reprograms Intratumoral Regulatory T Cells to Enhance Cancer Immunity / D. Wang, J. Quiros, K. Mahuron, C.C. Pai, V. Ranzani, A. Young, S. Silveria, T. Harwin, A. Abnousian, M. Pagani, M.D. Rosenblum, F. Van Gool, L. Fong, J.A. Bluestone, M. Dupage. - In: CELL REPORTS. - ISSN 2211-1247. - 23:11(2018 Jun), pp. 3262-3274.
open
Prodotti della ricerca::01 - Articolo su periodico
15
262
Article (author)
si
D. Wang, J. Quiros, K. Mahuron, C.C. Pai, V. Ranzani, A. Young, S. Silveria, T. Harwin, A. Abnousian, M. Pagani, M.D. Rosenblum, F. Van Gool, L. Fong,...espandi
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2434/693045
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