Nano-therapeutic cancer immunotherapy using hyperthermia-induced heat shock proteins: insights from mathematical modeling

Abstract

BackgroundNano-therapeutic utilizing hyperthermia therapy in combination with chemotherapy, surgery, and radiation is known to treat various types of cancer. These cancer treatments normally focus on reducing tumor burden. Nevertheless, it is still challenging to confine adequate thermal energy in a tumor and obtain a complete tumor ablation to avoid recurrence and metastasis while leaving normal tissues unaffected. Consequently, it is critical to attain an alternative tumor-killing mechanism to circumvent these challenges. Studies have demonstrated that extracellular heat shock proteins (HSPs) activate antitumor immunity during tumor cell necrosis. Such induced immunity was further shown to assist in regressing tumor and reducing recurrence and metastasis. However, only a narrow range of thermal dose is reported to be able to acquire the optimal antitumor immune outcome. Consequently, it is crucial to understand how extracellular HSPs are generated.Materials and methodsIn this work, a predictive model integrating HSP synthesis mechanism and cell death model is proposed to elucidate the HSP involvement in hyperthermia cancer immune therapy and its relation with dead tumor cells. This new model aims to provide insights into the thermally released extracellular HSPs by dead tumor cells for a more extensive set of conditions, including various temperatures and heating duration time.ResultsOur model is capable of predicting the optimal thermal parameters to generate maximum HSPs for stimulating antitumor immunity, promoting tumor regression, and reducing metastasis. The obtained nonlinear relation between extracellular HSP concentration and increased dead cell number, along with rising temperature, shows that only a narrow range of thermal dose is able to generate the optimal antitumor immune result.ConclusionOur predictive model is capable of predicting the optimal temperature and exposure time to generate HSPs involved in the antitumor immune activation, with a goal to promote tumor regression and reduce metastasis.

Hyperthermia Targeting the Tumor Microenvironment Facilitates Immune Checkpoint Inhibitors

“…They found that the maximum extracellular HSP synthesis was at 43°C, so was the maximum modulatory effect for tumor regression and decreased metastasis. When the temperature was further increased, HSP synthesis decreased, and the immune modulatory effect of hyperthermia was also downregulated (48). Whereas, through bioinformatic approach, Duzgun et al identified a series of molecules that determine the thermoresistance and immunogenic cell death in thermotherapy through estimating the percentage of the two kinds of denatured proteins.…”

“…They found that the maximum extracellular HSP synthesis was at 43°C, so was the maximum modulatory effect for tumor regression and decreased metastasis. When the temperature was further increased, HSP synthesis decreased, and the immune modulatory effect of hyperthermia was also downregulated ( 48 ). Whereas, through bioinformatic approach, Duzgun et al.…”

Immunogenic Effect of Hyperthermia on Enhancing Radiotherapeutic Efficacy

“…This effect of combination therapy was also validated in an in vivo mouse prostate cancer model [ 172 ]. Hyperthermia also increased extracellular Hsps during tumor necrosis, which induced immunity against tumor cells [ 173 ]. However, some studies reported the roles of Hsp70 in radioresistance and Hsp72 in etoposide-induced apoptosis resistance [ 174 , 175 ].…”

Use of microwave ablation for thermal treatment of solid tumors with different shapes and sizes—A computational approach

“…blood perfusion, electrical conductivity, and the cell death model, in the prediction of RFA zone size in the liver. Lin et al [34] utilized the three-state cell death model to predict the optimum temperature and exposure time that generates the maximum heat shock protein and reduces metastasis in nontherapeutic cancer immunotherapy by using hyperthermia.…”