A New Biomarker for Predicting the Abscopal Effect: Quantifying Polyclonal Effector Tumor Antigen-Specific T Cells by Using Nanoparticles Loading Whole Tumor Antigens

Radiation therapy (RT) plays important roles in cancer treatment, and the efficacy of RT depends on the abscopal effect, which results in the regression of distant and untreated tumors through localized irradiation of a single tumor lesion. This effect is mediated by effector tumor antigen-specific T cells (ETASTs) activated by RT. Monitoring the radiation-induced changes in ETASTs can be used to predict the abscopal effect. However, no precise and sensitive methods have been developed due to significant challenges. This is challenging because tumor antigens are highly heterogeneous, and thus, ETASTs are polyclonal and highly diverse. No structural differences exist between ETASTs and other T cells. Therefore, it is difficult to detect ETASTs in whole T cells. To overcome these limitations, we developed T cell-activating whole tumor-antigen-loaded nanoparticles (TATAN) to dynamically monitor RT-induced ETASTs. Tumor antigens in TATAN can specifically activate ETASTs in vitro during coincubation. Thus, the differences between ETASTs and other T cells are transformed into activated and nonactivated states. By measuring markers of the activated status and cytotoxic function of ETASTs, we can distinguish ETASTs from other T cells. In both breast cancer and lung cancer models, RT significantly enhanced the amount of ETASTs in the abscopal effect group in both tumor-draining lymph nodes (TDLNs) and splenocytes. Bulk RNA sequencing confirmed these results. This study establishes a new efficient biomarker for predicting the abscopal effect after RT. These findings potentially can be used to optimize RT strategies and understand the mechanisms underlying the abscopal effect.