Abstract
Immunotherapy has emerged as a therapeutic pillar in tumor treatment, but only a minority of patients get benefit. Overcoming the limitations of immunosuppressive environment is effective for immunotherapy. Moreover, host T cell activation and longevity within tumor are required for the long-term efficacy. In our previous study, a novel cryo-thermal therapy was developed to improve long-term survival in B16F10 melanoma and s.q. 4T1 breast cancer mouse models. We determined that cryo-thermal therapy induced Th1-dominant CD4+ T cell differentiation and the downregulation of Tregs in B16F10 model, contributing to tumor-specific and long-lasting immune protection. However, whether cryo-thermal therapy can affect the differentiation and function of T cells in a s.q. 4T1 model remains unknown. In this study, we also found that cryo-thermal therapy induced Th1-dominant differentiation of CD4+ T cells and the downregulation of effector Tregs. In particular, cryo-thermal therapy drove the fragility of Tregs and impaired their function. Furthermore, we discovered the downregulated level of serum tumor necrosis factor-α at the late stage after cryo-thermal therapy which played an important role in driving Treg fragility. Our findings revealed that cryo-thermal therapy could reprogram the suppressive environment and induce strong and durable antitumor immunity, which facilitate the development of combination strategies in immunotherapy.
Highlights
IntroductionCancer therapy has long depended on strategies that directly attack tumor cells
We revealed the effects of decreased serum tumor necrosis factor (TNF)-α on the fragility and function of Tregs after cryo-thermal therapy in a s.q. 4T1 breast cancer model
Our results indicated that cryo-thermal therapy could inhibit tumor metastasis and improve longterm survival, induce the differentiation of CD4+ T cells toward a Th1 polarizing phenotype, downregulate the proportion and suppressive function of Tregs and drive the fragility of Tregs
Summary
Cancer therapy has long depended on strategies that directly attack tumor cells. Cancer treatment has been revolutionized by the development of various immunotherapeutics. Cancer immunotherapy harnesses the patient’s immune system to fight cancer and provides a new treatment option in the therapeutic paradigm of surgery, radiotherapy, and chemotherapy. The therapeutic efficacy of immunotherapy is challenged by the low response rate and acquired resistance caused by tumor genetic instability [1]. One of the key factors that promote resistance is the suppressive tumor environment [2]. Ongoing immunotherapy studies are needed to develop strategies to overcome various immune tolerances and to promote the activation of host T cells
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