Abstract
Previous work using non-invasive radiofrequency field treatment (RFT) in cancer has demonstrated its therapeutic potential as it can increase intratumoral blood perfusion, localization of intravenously delivered drugs, and promote a hyperthermic intratumoral state. Despite the well-known immunologic benefits that febrile hyperthermia can induce, an investigation of how RFT could modulate the intra-tumoral immune microenvironment had not been studied. Thus, using an established 4T1 breast cancer model in immune competent mice, we demonstrate that RFT induces a transient, localized, and T-cell dependent intratumoral inflammatory response. More specifically we show that multi- and singlet-dose RFT promote an increase in tumor volume in immune competent Balb/c mice, which does not occur in athymic nude models. Further leukocyte subset analysis at 24, 48, and 120 hours after a single RFT show a rapid increase in tumoral trafficking of CD4+ and CD8+ T-cells 24 hours post-treatment. Additional serum cytokine analysis reveals an increase in numerous pro-inflammatory cytokines and chemokines associated with enhanced T-cell trafficking. Overall, these data demonstrate that non-invasive RFT could be an effective immunomodulatory strategy in solid tumors, especially for enhancing the tumoral trafficking of lymphocytes, which is currently a major hindrance of numerous cancer immunotherapeutic strategies.
Highlights
Results from this study further suggested that radiofrequency field treatment (RFT) promoted a unique form of tumor hyperthermia, with drastic improvements in temperature differential, uniform tumor heating, post-treatment intra-tumoral blood velocity, and overall safety compared to contact-convectively delivered hyperthermia treatment[16]
Based on our prior data, we have demonstrated that RFT can provide more localized, uniform, and safe intratumoral hyperthermia; an investigation of immunologic effects following febrile range RFT hyperthermia remains unstudied
With the emergence of immunotherapy as a promising cancer treatment modality there remains an evident need for immunomodulatory strategies capable of promoting effector immune cell trafficking and infiltration into solid tumors
Summary
Several potential treatment mechanisms have been suggested, including the ability of febrile range hyperthermia to improve tumor oxygenation: a critical hurdle of immune attack of solid tumors, as hypoxic conditions are known to promote many immunosuppressive effects[8,22]. The mechanism of this enhanced infiltration still remains somewhat unclear, prior data would suggest that the mild hyperthermia is able to drive various features which favor lymphocyte infiltration and attack of solid tumors; including increasing expression of vessel wall binding domains such as intercellular adhesion molecule-1 (ICAM-1)[24], promoting a more favorable intratumoral interstitial pressure[25], and driving the production of a number of pro-inflammatory cytokines and chemokines (i.e. interleukin (IL)−1β, IL-6, IL-8, IL-10) which have major implications in T-cell activation and trafficking[26,27]. Using immune competent Balb/c mice bearing 4T1 breast tumors we investigated both consecutive RFT dosing schedules and single-dose time-course investigations to better understand the transient immunologic changes induced by RFT
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