Histone deacetylase inhibitors prevent activation-induced cell death and promote anti-tumor immunity.
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.
Key Laboratory of Stem Cell Biology, Institute of Health Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences/Shanghai Jiao Tong University of Medicine, Shanghai, China.
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K
Cao
Key Laboratory of Stem Cell Biology, Institute of Health Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences/Shanghai Jiao Tong University of Medicine, Shanghai, China.
G
G
Wang
Key Laboratory of Stem Cell Biology, Institute of Health Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences/Shanghai Jiao Tong University of Medicine, Shanghai, China.
W
W
Li
Child Health Institute of New Jersey, Rutgers Robert Wood Johnson Medical School, New Brunswick, NJ, USA.|The First Affiliated Hospital of Soochow University, Institutes for Translational Medicine, Soochow University, Suzhou, China.
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L
Zhang
Uro-Oncology Research, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
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R
Wang
Key Laboratory of Stem Cell Biology, Institute of Health Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences/Shanghai Jiao Tong University of Medicine, Shanghai, China.
Y
Y
Huang
Key Laboratory of Stem Cell Biology, Institute of Health Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences/Shanghai Jiao Tong University of Medicine, Shanghai, China.
L
L
Du
The Third Affiliated Hospital of Soochow University, Changzhou, China.
J
J
Jiang
The Third Affiliated Hospital of Soochow University, Changzhou, China.
C
C
Wu
The Third Affiliated Hospital of Soochow University, Changzhou, China.
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X
He
Child Health Institute of New Jersey, Rutgers Robert Wood Johnson Medical School, New Brunswick, NJ, USA.
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AI
Roberts
Key Laboratory of Stem Cell Biology, Institute of Health Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences/Shanghai Jiao Tong University of Medicine, Shanghai, China.
F
F
Li
Child Health Institute of New Jersey, Rutgers Robert Wood Johnson Medical School, New Brunswick, NJ, USA.
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AB
Rabson
Key Laboratory of Stem Cell Biology, Institute of Health Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences/Shanghai Jiao Tong University of Medicine, Shanghai, China.
Y
Y
Wang
Key Laboratory of Stem Cell Biology, Institute of Health Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences/Shanghai Jiao Tong University of Medicine, Shanghai, China.|Child Health Institute of New Jersey, Rutgers Robert Wood Johnson Medical School, New Brunswick, NJ, USA.|The First Affiliated Hospital of Soochow University, Institutes for Translational Medicine, Soochow University, Suzhou, China.
Y
Y
Shi
D000818:Animals; D000906:Antibodies / Q000008:administration & dosage* / Q000627:therapeutic use; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000494:pharmacology; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects*; D060908:CTLA-4 Antigen / Q000037:antagonists & inhibitors*; D016923:Cell Death; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D053222:Fas Ligand Protein / Q000235:genetics / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D056572:Histone Deacetylase Inhibitors / Q000008:administration & dosage* / Q000494:pharmacology; D006801:Humans; D006877:Hydroxamic Acids / Q000008:administration & dosage / Q000494:pharmacology; D008546:Melanoma, Experimental / Q000188:drug therapy* / Q000276:immunology; D051379:Mice; D050778:NFATC Transcription Factors / Q000235:genetics / Q000378:metabolism
D000906:Antibodies; D000970:Antineoplastic Agents; D060908:CTLA-4 Antigen; D053222:Fas Ligand Protein; C505658:Fasl protein, mouse; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D050778:NFATC Transcription Factors; C494007:Nfatc2 protein, mouse; C012589:trichostatin A