Abstract
PurposeRadiofrequency ablation (RFA) is a minimally invasive energy delivery technique increasingly used for focal therapy to eradicate localized disease. RFA-induced tumor-cell necrosis generates an immunogenic source of tumor antigens known to induce antitumor immune responses. However, RFA-induced antitumor immunity is insufficient to control metastatic progression. We sought to characterize (a) the role of RFA dose on immunogenic modulation of tumor and generation of immune responses and (b) the potential synergy between vaccine immunotherapy and RFA aimed at local tumor control and decreased systemic progression.Experimental DesignMurine colon carcinoma cells expressing the tumor-associated (TAA) carcinoembryonic antigen (CEA) (MC38-CEA+) were studied to examine the effect of sublethal hyperthermia in vitro on the cells’ phenotype and sensitivity to CTL-mediated killing. The effect of RFA dose was investigated in vivo impacting (a) the phenotype and growth of MC38-CEA+ tumors and (b) the induction of tumor-specific immune responses. Finally, the molecular signature was evaluated as well as the potential synergy between RFA and poxviral vaccines expressing CEA and a TRIad of COstimulatory Molecules (CEA/TRICOM).Results In vitro, sublethal hyperthermia of MC38-CEA+ cells (a) increased cell-surface expression of CEA, Fas, and MHC class I molecules and (b) rendered tumor cells more susceptible to CTL-mediated lysis. In vivo, RFA induced (a) immunogenic modulation on the surface of tumor cells and (b) increased T-cell responses to CEA and additional TAAs. Combination therapy with RFA and vaccine in CEA-transgenic mice induced a synergistic increase in CD4+ T-cell immune responses to CEA and eradicated both primary CEA+ and distal CEA– s.c. tumors. Sequential administration of low-dose and high-dose RFA with vaccine decreased tumor recurrence compared to RFA alone. These studies suggest a potential clinical benefit in combining RFA with vaccine in cancer patients, and augment support for this novel translational paradigm.
Highlights
Thermal ablation techniques such as microwave, cryotherapy, laser ablation, high-intensity focused ultrasound (HIFU), and radiofrequency ablation (RFA) have been increasingly used for minimally invasive treatment of local unresectable tumors [1]
Combination therapy with RFA and vaccine in carcinoembryonic antigen (CEA)-transgenic mice induced a synergistic increase in CD4+ T-cell immune responses to CEA and eradicated both primary CEA+ and distal CEA– s.c. tumors
Ultra Low-Dose RFA Modulates Tumor Phenotype and CEA-Specific Immune Responses In Vivo we examined whether the phenotypic changes induced in vitro by exposure to sublethal hyperthermia could be captured by the gradient of thermal energy arising from treatment of MC38-CEA+ tumors with ultra-low dose RFA in vivo
Summary
Thermal ablation techniques such as microwave, cryotherapy, laser ablation, high-intensity focused ultrasound (HIFU), and radiofrequency ablation (RFA) have been increasingly used for minimally invasive treatment of local unresectable tumors [1]. RFA has proven to be safe and certain systems are cleared by the U.S Food and Drug Administration (FDA) for ablation of soft tissue, unresectable liver tumors, and painful lytic bone metastases. RFA employs an alternating RF current to generate frictional heat and induce coagulative necrosis within and surrounding solid tumors. This form of cell death is accompanied by release of inflammatory cytokines, and ‘‘danger signals’’ that can trigger and/or amplify pre-existing antitumor immunity [4,5,6]. Preclinical and clinical data suggest that RFA-induced necrosis is a source of tumor antigens that can be used by the host’s immune system to generate antitumor immunity [7]. Immune responses elicited by RFA alone are insufficient for morphologically visible responses or systemic control of tumor [8,9]
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