Combining Type I Interferons and 5-Aza-2′-Deoxycitidine to Improve Anti-Tumor Response against Melanoma

Abstract

Resistance to IFN-I-induced antineoplastic effects has been reported in many tumors and arises, in part, from epigenetic silencing of IFN-stimulated genes by DNA methylation. We hypothesized that restoration of IFN-stimulated genes by co-administration of the demethylating drug 5-aza-2'-deoxycitidine (decitabine [DAC]) may enhance the susceptibility to IFN-I-mediated antitumoral effects in melanoma. We show that combined administration of IFN-I and DAC significantly inhibits the growth of murine and human melanoma cells, both in vitro and in vivo. Compared with controls, DAC/IFN-I-treated melanoma cells exhibited reduced cell growth, augmented apoptosis, and diminished migration. Moreover, IFN-I and DAC synergized to suppress the growth of three-dimensional human melanoma spheroids, altering tumor architecture. These direct antitumor effects correlated with induction of the IFN-stimulated gene Mx1. In vivo, DAC/IFN-I significantly reduced melanoma growth via stimulation of adaptive immunity, promoting tumor-infiltrating CD8 T cells while inhibiting the homing of immunosuppressive CD11b myeloid cells and regulatory T cells. Accordingly, exposure of human melanoma cells to DAC/IFN-I induced the recruitment of immune cells toward the tumor in a Matrigel (Corning Life Sciences, Kennebunkport, ME)-based microfluidic device. Our findings underscore a beneficial effect of DAC plus IFN-I combined treatment against melanoma through both direct and immune-mediated anti-tumor effects.

The DNA methyltransferase inhibitor, guadecitabine, targets tumor-induced myelopoiesis and recovers T cell activity to slow tumor growth in combination with adoptive immunotherapy in a mouse model of breast cancer

“…Several groups have reported on the myelo-depleting properties of demethylating drugs such as decitabine [28,32] and 5-Azacitadine (AZA) [33], as well as other chemotherapy drugs, including gemcitabine [34,35], doxorubicin [8] and docetaxel [36]. Although MDSCs are not being directly targeted, they seem to be more susceptible to their effects as demonstrated in this study.…”

Immunomodulation by ionizing radiation—impact for design of radio‐immunotherapies and for treatment of inflammatory diseases

“…In contrast to that, induction and production of type I IFN in the tumor that initiates innate and adaptive immune attack on the tumor, is more linked to high single dose of radiation . Restoration of IFN‐stimulated genes is another feasible approach to generate anti‐tumor immune responses, as lately shown for melanoma . Ablative RT increases T‐cell priming in draining lymphoid tissues, resulting in reduction of the irradiated tumor as well as distant metastases .…”

“…141 Restoration of IFNstimulated genes is another feasible approach to generate anti-tumor immune responses, as lately shown for melanoma. 142 Ablative RT increases T-cell priming in draining lymphoid tissues, resulting in reduction of the irradiated tumor as well as distant metastases. 143 The same is observed for physico-chemical tumor ablation.…”

Systematic review and meta-analysis of prevalence of dermatological toxicities associated with vemurafenib treatment in patients with melanoma

“…Because only 11 studies met our inclusion criteria, the small number of trials and the low quality of most of them may make the conclusions less convincing. Publication bias could not be completely excluded based on Begg test . The researchers mostly based diagnosis of skin toxicities on the doctor's clinical judgement, and thus the same signs produced different opinions from different researchers.…”

“…Publication bias could not be completely excluded based on Begg test. 37 The researchers mostly based diagnosis of skin toxicities on the doctor's clinical judgement, and thus the same signs produced different opinions from different researchers. Finally, there was heterogeneity between studies in study protocol and vemurafenib doses, which could have led to significant heterogeneity in the data.…”