Cryo-thermal therapy elicits potent anti-tumor immunity by inducing extracellular Hsp70-dependent MDSC differentiation

Abstract

Achieving control of metastatic disease is a long-sought goal in cancer therapy. Treatments that encourage a patient’s own immune system are bringing new hopes in reaching such a goal. In clinic, local hyperthermia and cryoablation have been explored to induce anti-tumor immune responses against tumors. We have also developed a novel therapeutic modality of cryo-thermal treatment by alternating liquid nitrogen (LN2) cooling and radio frequency (RF) heating, and better therapeutic effect was achieved in treating metastatic cancer in animal model. In this study, we investigated the mechanism of systemic immune response elicited by cryo-thermal therapy. In the 4T1 murine mammary carcinoma model, we found that local cryo-thermal therapy resulted in a considerable reduction of distant lung metastases, and improved long-term survival. Moreover, results of tumor re-challenge experiments indicated generation of a strong tumor-specific immune memory after the local treatment of primary tumors. Our further study indicated that cryo-thermal therapy caused an elevated extracellular release of Hsp70. Subsequently, Hsp70 induced differentiation of MDSCs into mature DCs, contributing to the relief of MDSCs-mediated immunosuppression and ultimately the activation of strong anti-tumor immune response. Our findings reveal new insight into the mechanism of robust therapeutic effects of cryo-thermal therapy against metastatic cancers.

The Role of Myeloid-Derived Suppressor Cells in Viral Infection

“…Cryothermal therapy, in which cooling and heating are alternated, has been shown to lead to release of Hsp70, which induced differentiation of MDSCs into mature DCs, allowing for increased survival and decreased metastasis in a murine mammary carcinoma model (175).…”

The Heat Shock Protein Story—From Taking mTORC1,2 and Heat Shock Protein Inhibitors as Therapeutic Measures for Treating Cancers to Development of Cancer Vaccines

“…Using a transplantable mammary cancer cell line, the mammary metastatic lung cancer murine model was created [53]. A special combined hyper-and hypo-thermia program was tried on these animal models: 1) Radio frequency (RF) hyperthermia at 50˚C for 15 min; 2) hypothermia at −20˚C for 5 minutes; 3) then followed by RF heating again at 50˚C for 10 minutes.…”

Study of enhanced radiofrequency heating by pre-freezing tissue

“…Evidences show that RFA combined with cryosurgery has better therapeutic outcome in comparison to either ablation method alone and could even stimulate antitumor immunity [12][13][14]. Few articles have explained the essence of the enhancement of thermal ablation effects from the perspective of thermal physics.…”

“…Two locations near the center, but sufficiently spatially separate to have no effect on each other, were selected in each porcine liver for two different treatments: (a) RF heating without pre-freezing and (b) RF heating with pre-freezing. For the treatment of RF heating without pre-freezing, a commercial RF bipolar probe (Olympus-Celon, Germany) and an in-house RF generator [13,14] were used. The bipolar RF probe has an active length of 2 cm.…”

“…In our previous animal model study, we have found that RFA in pre-frozen tumor achieved a better therapeutic outcome. Pre-freezing tissue followed by RF heating treatment not only directly killed the tumor cells, but the tumor associated immune-suppression environment was also altered and anti-tumor immunity was stimulated [12][13][14]. Takahashi et al [15] have also found improved ablation using similar combination therapies.…”