To evaluate the efficacy and safety of toripalimab combined with neoadjuvant chemoradiotherapy (NCRT) for locally advanced esophageal squamous cell carcinoma (ESCC). In this single arm, phase II trial, 44 ESCC patients were enrolled from December 2019 to July 2021 at Sun Yat-sen University Cancer Center (Guangzhou, China). All patients received concurrent radiotherapy (44 Gy in 20 fractions), chemotherapy (paclitaxel 50 mg/m² and cisplatin 25 mg/m² on days 1, 8, 15, and 22), and toripalimab (240 mg on days 1 and 22). Within 6–8 weeks of neoadjuvant treatment, patients underwent surgery. The results of the study patients were compared with those of 86 matched patients between July 2015 and March 2022. The primary endpoint was pathological complete response (pCR) rate, and the secondary endpoints were treatment-related adverse events and R0 rates. This trail was registered with ClinicalTrails.gov, NCT04006041. All patients received neoadjuvant treatment, and 42 completed esophagectomy. Of the 42 patients, 21 (50%; 95% CI 35–65) achieved pCR and 2 (5%) patients were ypT0N+. The R0 resection rate was 98% (41/42). Nine (20%) of 44 patients had grade 3/4 adverse events. Among the perioperative complications (n = 42), anastomotic leakage occurred in five cases (12%), tracheal fistula in three cases (7%), and postoperative death in one case (2%) due to tracheal fistula. Compared with the control cohort, the pCR rate of the study group was higher but without significant difference (50% vs. 36%, P = 0.19). Toripalimab combined with NCRT failed to show significantly better pCR rate than historical data. Nevertheless, considering the signs of efficacy and acceptable safety of this regimen, further evaluation in phase III randomized trials might be warranted. 10.13039/501100001809 National Natural Science Foundation of China .

Neoadjuvant chemoradiotherapy (neoCRT) followed by surgery is the most common approach for locally advanced resectable esophageal squamous cell carcinoma (ESCC) patients. How neoCRT impacts ESCC tumor immune microenvironment (TIME) has not been fully understood. Single-cell RNA sequencing (scRNA-seq) was conducted to examine the neoCRT-driven cellular and molecular dynamics in 8 pre- and 7 post-neoCRT ESCC samples from 8 male patients. scRNA-seq data of about 112,000 cells were obtained. Expression programs of cell cycle, epithelium development, immune response, and extracellular structure in pre-treatment tumor cells were related to neoCRT response. Spearman correlation between CD8⁺ T cells' cytotoxicity and expression of checkpoint molecules was prominent in pre-neoCRT intermediate activated/exhausted CD8⁺ T cells. NeoCRT increased CD8⁺ T cells’ infiltration but promoted their exhaustion in both major and minor responders. NeoCRT promoted differentiation of Th but demoted that of Treg cells in major responders. Maturation of cDC1s and expression of M2 macrophage markers increased while the number of cDC2s decreased after neoCRT. Higher activities of immune-related pathways in pre-neoCRT CD8⁺ T cells and macrophages, as well as a pronounced decrease of them after neoCRT, correlated with better neoCRT response. Interactions between intermediate activated/exhausted CD8⁺ T and macrophages, cDC1s, and LAMP3⁺ cDCs decreased after neoCRT. Our comprehensive picture of the neoCRT-related immune changes provides deeper insights into immunological mechanisms associated with ESCC response to neoCRT, which may aid in future development of immune-strategies for improving ESCC treatment. This work was supported by the National Natural Science Foundation of China (82072607).

TRPV6 is over-expressed and promotes the proliferation and invasion in many cancers. The association between the expression of TRPV6 and clinical outcome in esophageal squamous cell carcinoma (ESCC) has not been studied yet. We aim to elucidate the role of TRPV6 in predicting prognosis of patients with ESCC. In the retrospective study, mRNA level of TRPV6 was examined in patients (N = 174) from Sun Yat-sen University Cancer Center (mRNA cohort) and protein level of TRPV6 was examined in patients (N = 218) from Linzhou Cancer Hospital (protein cohort). Statistical analysis was performed to test the clinical and prognostic significance of TRPV6. TRPV6 was down-regulated in ESCC tissues and cell lines. Patients with downregulation of TRPV6 trended to have a higher rate of advanced pT stage in both mRNA cohort (P = 0.089) and protein cohort (P = 0.073), though not statistically significant. No significant association was observed between TRPV6 expression and disease-specific survival (DSS) in both two cohorts. However, stratified survival analysis based on the gender showed that in mRNA cohort, downregulation of TRPV6 was associated with an unfavorable 3-year DSS in patients with male (47.3 % vs 63.6 %, P = 0.027) and with favorable 3-year DSS in patients with female (66.7 % vs 43.0 %, P = 0.031). The result was confirmed in protein cohort. Male patients with downregulation of TRPV6 had a poor 3-year DSS (20.0 % vs 57.1 %,P < 0.001) while female counterparts showed an enhanced 3-year DSS (56.1 % vs 28.6 %, P = 0.005). TRPV6 is down-regulated in ESCC. As a predictive biomarker, TRPV6 plays a Janus-like role in predicting survival of male and female ESCC patients.

Background: Hepatitis B Virus (HBV) infection has been proven to be associated with the survival of many cancers. However, the prevalence and prognostic value of HBV infection in esophageal cancer has not been investigated yet. Methods: A total of 2,004 consecutive esophageal cancer patients who underwent esophagectomy between 2000 and 2008 were recruited in our study. ELISA was used to test serum HBV markers. Patients were divided into HBsAg-positive group (HBV infection) and HBsAg-negative group. The impact of HBV infection on disease-free survival (DFS) and overall survival (OS) was estimated using the Kaplan–Meier method and Cox proportional hazard models. Results: HBV infection was found in 12.6% (253/2,004) of patients. HBsAg-positive patients had significantly higher percentage of early pathologic T stage, lower frequency of liver metastasis, and extrahepatic metastasis than HBsAg-negative. HBsAg-positive patients had a favorable DFS [HR = 0.79; 95% confidence interval (CI): 0.66–0.94, P = 0.007) and OS (HR = 0.80; 95% CI: 0.65–0.95, P = 0.020] respectively, when compared with HBsAg-negative patients. Subgroup analysis showed that the association with HBV infection and better DFS and OS was observed in patients with esophageal squamous cell carcinoma and advanced pathologic stage (III–IV). Conclusion: HBV infection was an independent favorable prognostic factor for survival in operable esophageal cancer. Impact: Our large cohort study provided more definite and quantitative evidence that HBV infection is an independent favorable prognostic biomarker in patients with esophageal cancer, especially in patients with esophageal squamous cell carcinoma and advanced pathologic stage (III–IV).