Safety and efficacy of neoadjuvant radiotherapy and immunotherapy in the treatment of esophageal squamous cell carcinoma
Background: Immunotherapy has been employed in the neoadjuvant treatment of locally advanced esophageal squamous cell carcinoma. To assess the feasibility of neoadjuvant radiotherapy combined with immunotherapy (NRIT), this study compares the efficacy and effectiveness of neoadjuvant chemoradiotherapy combined with immunotherapy (NICRT) and NRIT, while also exploring the underlying mechanisms of NRIT. Methods:This study retrospectively analyzed a cohort of 64 patients diagnosed with locally advanced esophageal squamous cell carcinoma (ESCC) who underwent neoadjuvant therapy followed by esophagectomy between January 2019 and September 2023. Of these, 26 patients received neoadjuvant radiotherapy and immunotherapy (NRIT), while 38 patients were treated with neoadjuvant chemoradiotherapy (NICRT). The final analysis included pathological complete response (pCR), major pathological response (MPR), tumor regression grade (TRG), the rate of positive lymph node pCR, toxicity, surgical outcomes, postoperative complications, disease-free survival (DFS), and overall survival (OS). Additionally, paraffin-embedded tissue sections obtained before and after neoadjuvant NRIT were subjected to whole-exome sequencing, transcriptome sequencing, and immunohistochemistry (IHC) for programmed death-ligand 1 (PD-L1) analysis. Results: There was no significant difference in the rates of MPR and PCR (28.95% vs 30.77%, P=0.873), TRG classification (P=0.338), surgical outcomes, or postoperative complications (P=0.148), as well as overall survival (OS) and disease-free survival (DFS) between the NICRT and NRIT groups. However, a notable difference was observed in grade 3 or higher adverse events during treatment, with the NICRT group experiencing a higher incidence (34.21% vs 7.69%, P = 0.017) and severe hematological toxicity (23.68% vs 0.00%, P = 0.008). In the NRIT group, patients with high CPS scores demonstrated improved pathological responses. Pre-treatment genomic analyses indicated no differences in tumor mutation burden (TMB), somatic mutations, and copy number variations between MPR and non-MPR patients post-surgery. Transcriptome analysis revealed a significant number of differentially expressed genes in patients before and after treatment, closely associated with key pathways related to immunity. Following treatment, MPR patients exhibited a marked upregulation of the type I interferon response and the MHC class I antigen presentation pathway. Additionally, the number of B cells and monocytes increased, while non-MPR patients showed a significant downregulation of dendritic cells (DCs) after treatment, alongside the activation of various immune cells, including CD8 naïve cells, NK cells, and B cells. Conclusion: There was no significant difference between the NRIT group and the NICRT group regarding pathological response, surgical outcomes, postoperative complications, and survival analysis; furthermore, NRIT demonstrated a better safety profile compared to NICRT during treatment. Additionally, the mechanism of action of NRIT has been elucidated through a comprehensive analysis of genomic, transcriptomic, immunohistochemical, and other methods in conjunction with clinical results, thereby establishing NRIT as a neoadjuvant treatment that is both effective and safe. Overall design: Patients receiving NRIT were subjected to whole-exome sequencing, RNA sequencing, and immunohistochemistry (IHC) analysis of programmed death-ligand 1 (PD-L1) on paraffin-embedded tissue sections obtained before and after treatment. The RNA sequencing included 14 pretreatment samples (RNA1-14) and 15 post-treatment samples (RNA15-29).