IFNγ at the early stage induced after cryo-thermal therapy maintains CD4 Th1-prone differentiation, leading to long-term antitumor immunity.

Introduction: Recently, more and more research illustrated the importance of inducing CD4 T helper type (Th)-1 dominant immunity for the success of tumor immunotherapy. Our prior studies revealed the crucial role of CD4 Th1 cells in orchestrating systemic and durable antitumor immunity, which contributes to the satisfactory outcomes of the novel cryo-thermal therapy in the B16F10 tumor model. However, the mechanism for maintaining the cryo-thermal therapy-mediated durable CD4 Th1-dominant response remains uncovered. Additionally, cryo-thermal-induced early-stage CD4 Th1-dominant T cell response showed a correlation with the favorable prognosis in patients with colorectal cancer liver metastasis (CRCLM). We hypothesized that CD4 Th1-dominant differentiation induced during the early stage post cryo-thermal therapy would affect the balance of CD4 subsets at the late phase.

Methods: To understand the role of interferon (IFN)-γ, the major effector of Th1 subsets, in maintaining long-term CD4 Th1-prone polarization, B16F10 melanoma model was established in this study and a monoclonal antibody was used at the early stage post cryo-thermal therapy for interferon (IFN)-γ signaling blockade, and the influence on the phenotypic and functional change of immune cells was evaluated.

Results: IFNγ at the early stage after cryo-thermal therapy maintained long-lasting CD4 Th1-prone immunity by directly controlling Th17, Tfh, and Tregs polarization, leading to the hyperactivation of Myeloid-derived suppressor cells (MDSCs) represented by abundant interleukin (IL)-1β generation, and thereby further amplifying Th1 response.

Discussion: Our finding emphasized the key role of early-phase IFNγ abundance post cryo-thermal therapy, which could be a biomarker for better prognosis after cryo-thermal therapy.