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Histone deacetylase inhibitors prevent activation-induced cell death and promote anti-tumor immunity.

ABSTRACT: The poor efficacy of the in vivo anti-tumor immune response has been partially attributed to ineffective T-cell responses mounted against the tumor. Fas-FasL-dependent activation-induced cell death (AICD) of T cells is believed to be a major contributor to compromised anti-tumor immunity. The molecular mechanisms of AICD are well-investigated, yet the possibility of regulating AICD for cancer therapy remains to be explored. In this study, we show that histone deacetylase inhibitors (HDACIs) can inhibit apoptosis of CD4(+) T cells within the tumor, thereby enhancing anti-tumor immune responses and suppressing melanoma growth. This inhibitory effect is specific for AICD through suppressing NFAT1-regulated FasL expression on activated CD4(+) T cells. In gld/gld mice with mutation in FasL, the beneficial effect of HDACIs on AICD of infiltrating CD4(+) T cells is not seen, confirming the critical role of FasL regulation in the anti-tumor effect of HDACIs. Importantly, we found that the co-administration of HDACIs and anti-CTLA4 could further enhance the infiltration of CD4(+) T cells and achieve a synergistic therapeutic effect on tumor. Therefore, our study demonstrates that the modulation of AICD of tumor-infiltrating CD4(+) T cells using HDACIs can enhance anti-tumor immune responses, uncovering a novel mechanism underlying the anti-tumor effect of HDACIs.

SUBMITTER: Cao K

PROVIDER: S-EPMC4672172 | biostudies-literature | 2015 Dec

REPOSITORIES: biostudies-literature

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Histone deacetylase inhibitors prevent activation-induced cell death and promote anti-tumor immunity.

Cao K K Wang G G Li W W Zhang L L Wang R R Huang Y Y Du L L Jiang J J Wu C C He X X Roberts A I AI Li F F Rabson A B AB Wang Y Y Shi Y Y

Oncogene 20150309 49

The poor efficacy of the in vivo anti-tumor immune response has been partially attributed to ineffective T-cell responses mounted against the tumor. Fas-FasL-dependent activation-induced cell death (AICD) of T cells is believed to be a major contributor to compromised anti-tumor immunity. The molecular mechanisms of AICD are well-investigated, yet the possibility of regulating AICD for cancer therapy remains to be explored. In this study, we show that histone deacetylase inhibitors (HDACIs) can ...[more]

PMID: 25745993

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Histone deacetylase inhibitors prevent activation-induced cell death and promote anti-tumor immunity.

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Histone deacetylase inhibitors prevent activation-induced cell death and promote anti-tumor immunity.

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