Potential Predictive Immune and Metabolic Biomarkers of Tumor Microenvironment Regarding Pathological and Clinical Response in Esophageal Cancer After Neoadjuvant Chemoradiotherapy: A Systematic Review

Abstract

Introduction: The tumor microenvironment (TME) plays a crucial role in therapy response and modulation of immunologic surveillance. Adjuvant immunotherapy has recently been introduced in post-surgery treatment of locally advanced esophageal cancer (EC) with residual pathological disease after neoadjuvant chemoradiotherapy (nCRT). F-18 fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG-PET/CT) remains a valuable imaging tool to assess therapy response and to visualize metabolic TME; however, there is still a paucity in understanding the interaction between the TME and nCRT response. This systematic review investigated the potential of TME biomarkers and 18F-FDG-PET/CT features to predict pathological and clinical response (CR) after nCRT in EC. Methods: A literature search of the Medline and Embase electronic databases identified 4190 studies. Studies regarding immune and metabolic TME biomarkers and 18F-FDG-PET/CT features were included for predicting pathological response (PR) and/or CR after nCRT. Separate analyses were performed for 18F-FDG-PET/CT markers and these TME biomarkers. Results: The final analysis included 21 studies—10 about immune and metabolic markers alone and 11 with additional 18F-FDG-PET/CT features. High CD8 infiltration before and after nCRT, and CD3 and CD4 infiltration after nCRT, generally correlated with better PR. A high expression of tumoral or stromal programmed death-ligand 1 (PD-L1) after nCRT was generally associated with poor PR. Moreover, total lesion glycolysis (TLG) and metabolic tumor volume (MTV) of the primary tumor were potentially predictive for clinical and PR. Conclusion: CD8, CD4, CD3, and PD-L1 are promising immune markers in predicting PR, whereas TLG and MTV are potential 18F-FDG-PET/CT features to predict clinical and PR after nCRT in EC.