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Background In esophageal cancer (EC), there is a paucity of knowledge regarding the interplay between the tumor immune microenvironment and response to neoadjuvant treatment and, therefore, which factors may influence outcomes. Thus, our goal was to investigate the changes in the immune microenvironment with neoadjuvant treatment in EC by assessing the expression of immune related genes and their association with prognosis. Methods We examined the transcriptome of paired pre- and post-neoadjuvant treated EC specimens. Based on these findings, we validated the presence of tumor-infiltrating neutrophils using CD15+ immunohistochemistry in a discovery cohort of patients with residual pathologic disease. We developed a nomogram as a predictor of progression-free survival (PFS) incorporating the variables CD15+ cell count, tumor regression grade, and tumor grade. Results After neoadjuvant treatment, there was an increase in genes related to myeloid cell differentiation and a poor prognosis associated with high neutrophil (CD15+) counts. Our nomogram incorporating CD15+ cell count was predictive of PFS with a C-index of 0.80 (95% confidence interval [CI] 0.68–0.9) and a concordance probability estimate (CPE) of 0.77 (95% CI 0.69–0.86), which indicates high prognostic ability. The C-index and CPE of the validation cohort were 0.81 (95% CI 0.69–0.91) and 0.78 (95% CI 0.7–0.86), respectively. Conclusions Our nomogram incorporating CD15+ cell count can potentially be used to identify patients at high risk of recurrent disease and thus stratify patients who will benefit most from adjuvant treatment.

Heat shock protein 70 (Hsp70) is a well-known inhibitor of apoptotic pathways; however, a role for Hsp70 in the modulation of death receptor-mediated apoptosis remains largely unexplored. In this study, the ability of Hsp70 to modulate tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL)-induced apoptosis was examined in SW480 and CCRF-CEM cells. These lines exhibit the characteristics of type I cells (SW480, human colon adenocarcinoma), with no requirement for mitochondrial involvement to exhibit apoptosis following death receptor engagement and type II cells (CCRF-CEM, human leukemic T cell), which do require amplification of the signal through the mitochondria. Unexpectedly, expression of Hsp70 in the type II CCRF-CEM cells enhanced the extent of TRAIL-induced apoptosis, but in SW480, Hsp70 had no impact on TRAIL-induced apoptosis. The enhanced TRAIL-induced apoptosis was accompanied by an up-regulation of TRAIL receptors, R1 and R2, at the cell surface as determined by flow cytometry and at the transcriptional level as assessed by real-time polymerase chain reaction (PCR). Increased expression of Hsp70 led to up-regulated expression of p53, and chromatin immunoprecipitation combined with real-time PCR revealed increased binding of p53 to its consensus sequence in the TRAIL-R2 gene. In contrast, expression of Hsp70 in SW480 cells did not increase p53 or TRAIL-R1 or TRAIL-R2 surface expression. This result is in marked contrast to most apoptotic stresses, including TNFalpha and Fas ligand, where Hsp70 has been shown to inhibit apoptosis in type II cells. These findings suggest that in tumors retaining functional p53 and expressing high levels of Hsp70, TRAIL may be an effective therapy.