Abstract
Modulated electro-hyperthermia (mEHT), induced by 13.56 MHz radiofrequency, has been demonstrated both in preclinical and clinical studies to efficiently induce tumor damage and complement other treatment modalities. Here, we used a mouse xenograft model of human melanoma (A2058) to test mEHT (~42°C) both alone and combined with NK-cell immunotherapy. A single 30 min shot of mEHT resulted in significant tumor damage due to induced stress, marked by high hsp70 expression followed by significant upregulation of cleaved/activated caspase-3 and p53. When mEHT was combined with either primary human NK cells or the IL-2 independent NK-92MI cell line injected subcutaneously, the accumulation of NK cells was observed at the mEHT pretreated melanoma nodules but not at the untreated controls. mEHT induced the upregulation of the chemoattractant CXCL11 and increased the expression of the matrix metalloproteinase MMP2 which could account for the NK-cell attraction into the treated melanoma. In conclusion, mEHT monotherapy of melanoma xenograft tumors induced irreversible heat and cell stress leading to caspase dependent apoptosis to be driven by p53. mEHT could support the intratumoral attraction of distantly injected NK-cells, contributed by CXCL11 and MMP2 upregulation, resulting in an additive tumor destruction and growth inhibition. Therefore, mEHT may offer itself as a good partner for immunotherapy.
Highlights
Modulated electro-hyperthermia is an effective and safe form of hyperthermia, which aims at selective heating of the extracellular matrix and cell membranes in the malignant tissues rather than homogenous heat delivery into tumors [1]
In a recently published paper, we described the effect of Modulated electro-hyperthermia (mEHT) on B16F10, a mouse melanoma cell line, in vitro and in vivo [2, 31]
We make use of immunodeficient NOD/SCID mice to extend our studies on the effectiveness of mEHT on human melanoma using the A2058 cell line and, to investigate the role of mEHT in combination with Natural killer (NK) cell immunotherapy
Summary
Modulated electro-hyperthermia (mEHT) is an effective and safe form of hyperthermia, which aims at selective heating of the extracellular matrix and cell membranes in the malignant tissues rather than homogenous heat delivery into tumors [1]. Electro-Hyperthermia Facilitated NK-Cell Infiltration papers have described the growth inhibiting effect of mEHT in various tumor types, mostly in preclinical mouse models [2,3,4,5,6]. These results provide evidence that besides the direct cell killing, mEHT has an immunomodulatory effect supporting the antitumor immune response [3, 4, 7]. Natural killer (NK) cell therapy represents a promising novel treatment modality for both hematological malignancies and solid tumors [12]. In a recent study Yang et al has reported that the focused ultrasound enhanced the accumulation of NK cells in ovarian cancer xenograft mainly by inducing CX3CL1 expression [18]
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