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.

HDACs and HDAC Inhibitors in Cancer Development and Therapy

“…The efficacy of HDACi can be significantly enhanced by the concurrent administration of various immunotherapeutic approaches, such as cancer vaccines, adoptive T-cell transfer and immune checkpoint inhibitors (Park et al 2015). For example, co-administration of HDACi with antibodies against cytotoxic T-lymphocyte antigen 4 (CTLA4) could further enhance the infiltration of CD4+ T cells and achieve a synergistic therapeutic effect on tumors by promoting antitumor immune responses (Cao et al 2015). A recent preclinical study indicated that HDACi in combination with immunomodulatory drugs, such as lenalidomide and pomalidomide, showed a synergistic cytotoxicity in multiple myeloma by downregulating c-Myc expression.…”

Targeting Histone Deacetylases in Malignant Melanoma: A Future Therapeutic Agent or Just Great Expectations?

“…In this study TSA was approved, the first FDAapproved HDACI that causes down-regulation of FasL expression on infiltrating CD4 + T cells, to inhibit the apoptosis of CD4 + T lymphocytes. Additionally, the same study showed that TSA and CTLA4 antibody act synergistically to enhance CD4 + T-cell infiltration and that TSA can increase the expression of Il-2, TNF-a and GH-CSF, cytokines associated with cell activation (23).…”

“…Butyrate as well as trichostatin A inhibited the cell growth mainly by arresting the cell cycle and the cell invasion was inhibited by butyrate and trichostatin A. At low doses, sodium butyrate and trichostatin induced a G 1 cellcycle block in melanoma cells (23).…”

“…It also increases the expression of Il-2, TNF-a, GM-CSF and the activation of T-cells. Moreover, TSA induces autophagy in cells through inhibition of rapamycin motor pathway (22) and inhibits apoptosis of activated CD4 + T lymphocytes (23). Butyrate as well as trichostatin A inhibited the cell growth mainly by arresting the cell cycle and the cell invasion was inhibited by butyrate and trichostatin A.…”

Discovery and Development of HDAC Subtype Selective Inhibitor Chidamide: Potential Immunomodulatory Activity Against Cancers

“…Other findings that the benzamide type of Class I HDAC inhibitors can decrease the number of MDSC, induce PD-L1 expression in tumour cells and decrease expression of PD-1 expression in CD4 + T cell and increase filtration of CD8 + T cells into tumour tissues, are all pointing to their potential to synergise with other treatment regimens including most recent developed checkpoint inhibitor of immunotherapy. Based on the advances made in this field, we have summarised a historic progress of key advances of HDAC inhibitor on cancer immunomodulatory activity in Figure 5.8 [15,24,[48][49][50][51][52][53][54][55].…”