Peripheral CD8 + PD-1 + T cells as novel biomarker for neoadjuvant chemoimmunotherapy in humanized mice of non-small cell lung cancer

Abstract Background Neoadjuvant immunotherapy has shown promising clinical activity in the treatment of early non-small cell lung cancer (NSCLC); however, further clarification of the specific mechanism and identification of biomarkers are imperative prior to implementing it as a daily practice. Methods We investigated the impact of neoadjuvant chemoimmunotherapy (combining cisplatin with pembrolizumab) on an established preclinical NSCLC mouse model engrafted with human immune system, and explored its potential mechanism. We further explored potential biomarkers for neoadjuvant therapy and conducted in vivo validation using the model. In addition, both peripheral blood and tumor specimens from 14 patients undergoing neoadjuvant chemoimmunotherapy were analyzed to validate our findings. Results Neoadjuvant chemoimmunotherapy could prevent postoperative recurrence and metastasis by increasing the frequency and activation of CD8+ T cells in both peripheral blood and tumor immune microenvironment (TIME). The kinetics of peripheral CD8+PD-1+ T cells reflected the changes in the TIME and pathological responses, ultimately predicting survival outcome of mice. Further analysis of clinical specimens not only confirmed the reprogramming of TIME, but also validated CD8+PD-1+ T cells as rational biomarker. Conclusions The kinetics of peripheral CD8+ T cells can serve as a predictor for changes in TIME and overall antitumor immune responses, ultimately reflecting the outcomes of neoadjuvant chemoimmunotherapy in both preclinical and clinical setting. Our findings establish a theoretical foundation for the clinical translation of this promising biomarker.