Department of Chemistry and Biochemistry, University of California, Los Angeles, CA, USA.
Int J Nanomedicine. 2018 Jun 19;13:3529-3539. doi: 10.2147/IJN.S166000. eCollection 2018.
Nano-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.
In 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.
Our 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.
Our 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.
利用热疗联合化疗、手术和放疗的纳米治疗被用于治疗各种类型的癌症。这些癌症治疗通常侧重于减少肿瘤负担。然而，在肿瘤中充分集中热能并获得完全肿瘤消融以避免复发和转移，同时不影响正常组织，仍然具有挑战性。因此，获得替代肿瘤杀伤机制来规避这些挑战至关重要。研究表明，细胞外热休克蛋白（HSPs）在肿瘤细胞坏死时激活抗肿瘤免疫。这种诱导的免疫进一步被证明有助于肿瘤消退和减少复发和转移。然而，只有报告了很窄的热剂量范围才能获得最佳的抗肿瘤免疫效果。因此，了解细胞外 HSPs 是如何产生的至关重要。
在这项工作中，提出了一个整合 HSP 合成机制和细胞死亡模型的预测模型，以阐明 HSPs 在热疗癌症免疫治疗中的作用及其与死亡肿瘤细胞的关系。这个新模型旨在为更广泛的条件下（包括各种温度和加热持续时间）由死亡肿瘤细胞释放的热激蛋白提供深入了解。
我们的模型能够预测产生最大 HSPs 以刺激抗肿瘤免疫、促进肿瘤消退和减少转移的最佳热参数。获得的细胞外 HSP 浓度与死亡细胞数量增加之间的非线性关系，以及温度升高，表明只有很窄的热剂量范围才能产生最佳的抗肿瘤免疫效果。
我们的预测模型能够预测产生参与抗肿瘤免疫激活的 HSPs 的最佳温度和暴露时间，以促进肿瘤消退和减少转移。
