Abstract
BackgroundThe immunogenomic changes triggered by concurrent chemoradiation therapy (CCRT), a standard neoadjuvant treatment for locally advanced esophageal squamous cell carcinoma (ESCC), are unknown. We aimed to analyze the early immunogenomic changes in ESCC induced by CCRT and to correlate them with clinical outcomes.MethodsWe collected biopsy samples from 40 patients with ESCC and the surgical candidates were treated with 5-fluorouracil (5-FU)/Cisplatin and concurrent radiation therapy. Endoscopic biopsy was performed before and after one treatment cycle of 5-FU/Cisplatin and 5 to 18 fractions of radiation. We analyzed immunogenomic changes using paired whole-exome sequencing (n = 29) and paired whole-transcriptome sequencing (WTS, n = 23). Multiplex immunohistochemistry (IHC) was conducted in four representative pair samples.ResultsFourteen out of 23 WTS samples (60.8%) showed increased immune scores after CCRT, as calculated by ESTIMATE. The rate of progression-free survival was higher in patients with increased immune scores compared with the remaining patients (83.1% vs. 57.1%, p = 0.25). Tumor mutation burden and neoantigen load were significantly reduced after CCRT (p < 0.001). We observed no specific correlation with non-synonymous mutations and no changes in the single-nucleotide variant spectrum after CCRT. Post-CCRT samples were enriched in gene sets related to immune signaling pathways, such as interferon gamma signaling and CD28 co-stimulation. Multiplex IHC showed an incremental trend in the proportion of CD4 positive cells in cytokeratin positive region after CCRT. However, CD8, CD20, FOXP1, PD-L1 showed no definitive trend. Proportion of immune cells calculated by CIBERSORT, showed that significant increase in neutrophils after CCRT.ConclusionsWe have comprehensively analyzed the early immunogenomic changes induced in ESCC by CCRT and correlated them with clinical outcomes. Our results provide a potential basis for combining immunotherapy with CCRT for the treatment of ESCC.
Highlights
The immunogenomic changes triggered by concurrent chemoradiation therapy (CCRT), a standard neoadjuvant treatment for locally advanced esophageal squamous cell carcinoma (ESCC), are unknown
The first biopsy was conducted at a median time of 4 days before CCRT and the second biopsy was conducted at a median of 18 days after CCRT
Seventeen patients are currently enrolled in other clinical trial, which aims to study the effects of randomized adjuvant durvalumab treatment versus placebo (NCT02520453; Additional file 1: Table S1) [36]
Summary
The immunogenomic changes triggered by concurrent chemoradiation therapy (CCRT), a standard neoadjuvant treatment for locally advanced esophageal squamous cell carcinoma (ESCC), are unknown. The combined modality approach of preoperative concurrent chemoradiation therapy (CCRT) and surgery has shown superior clinical outcomes compared with surgery or chemotherapy alone for the treatment of locally advanced ESCC [2,3,4]. The underlying immunogenomic changes induced by CCRT in the tumor and its microenvironment remain unknown. Analysis of such changes may offer additional insights into the synergistic effects of immunotherapy and CCRT and provide potential predictive or prognostic biomarkers [8]
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