Esophageal squamous cell carcinoma (ESCC) is one of the common malignant tumors in the world. More than half of patients with ESCC were detected in advanced or metastatic disease at the time of initial diagnosis and lost the opportunities of surgery. Currently, surgical resection, radiotherapy, and chemotherapy are most utilized in clinical practice, however, they are associated with limited survival benefits. Recognition of the limitation of traditional antitumor strategies prompt the development of new means to treat human cancer. In recent years, studies on immune checkpoint inhibitors (eg PD-1/PD-L1 inhibitors, CTLA-4 inhibitors, etc.) in ESCC have shown promising results. In addition, the combination of immune checkpoint inhibitor and traditional antitumor strategies for ESCC has caused extensive interest, and the results are encouraging. Previous analysis indicated that tumor cell PD-L1 expression, tumor mutation load (TMB), microsatellite instability-high status (MSI-H), and other biomarkers have relatively correlated with the efficacy of immunotherapy. This review explores the recent studies investigating checkpoint inhibitors in ESCC.

Overcoming resistance to radiation is a great challenge in cancer therapy. Here, we highlight that targeting valosin‐containing protein (VCP) improves radiation sensitivity in esophageal squamous cell carcinoma (ESCC) cell lines and show the potential of using VCP as a prognosis marker in locally advanced ESCC treated with radiation therapy. Esophageal squamous cell carcinoma cell lines with high VCP expression were treated with VCP inhibitor combined with radiotherapy. Cell proliferation, colony formation, cell death, and endoplasmic reticulum (ER) stress signaling were evaluated. Moreover, patients with newly diagnosed locally advanced ESCC who were treated with radiotherapy were analyzed. Immunohistochemistry was used to detect the expression of VCP. The correlation between overall survival and VCP was investigated. Esophageal squamous cell carcinoma cells treated with VCP inhibitor and radiotherapy showed attenuated cell proliferation and colony formation and enhanced apoptosis. Further investigation showed this combined strategy activated the ER stress signaling involved in unfolded protein response, and inhibited the ER‐associated degradation (ERAD) pathway. Clinical analysis revealed a significant survival benefit in the low VCP expression group. Targeting VCP resulted in antitumor activity and enhanced the efficacy of radiation therapy in ESCC cells in vitro. Valosin‐containing protein is a promising and novel target. In patients with locally advanced ESCC who received radiotherapy, VCP can be considered as a useful prognostic indicator of overall survival. Valosin‐containing protein inhibitors could be developed for use as effective cancer therapies, in combination with radiation therapy.

Indoleamine 2,3-dioxygenase (IDO1) plays an important role in tumor immune evasion. In this study, we investigated the changes of tumor IDO1 expression and CD8+ tumor-infiltrating lymphocytes (TILs) status in tumor microenvironment (TME) after neoadjuvant chemoradiotherapy (NCRT) or neoadjuvant chemotherapy (NCT) in esophageal squamous cell carcinoma (ESCC), respectively. Moreover, the potential predictive value of the changes of tumor IDO1 expression and CD8+TILs status on pathologic response and clinical outcome was further evaluated. By matching propensity scores in 295 patients, a total of 85 ESCC patients with neoadjuvant therapy followed by surgery were recruited, including 17 patients with NCRT and 68 patients with NCT. Tumor IDO1 expression and CD8+TILs within TME in paired specimens were evaluated by immunohistochemistry, and the changes of tumor IDO1 expression and CD8+TILs between the paired specimens were estimated. Tumor IDO1 expression significantly increased from baseline to postoperative tumor tissue after NCT ( p = 0.002), whereas no significant difference was detected after NCRT ( p = 0.44). The density of CD8+TILs in the tumor-invasive margin increased significantly after neoadjuvant therapy, and there was no significant difference in density changes of CD8+TILs between the NCRT and NCT groups ( p = 0.118). Upregulation of tumor IDO1 expression after neoadjuvant therapy was associated with poor pathologic response ( p = 0.002). Lastly, multivariate Cox analysis showed that IDO1-rise patients after neoadjuvant therapy were related to poor prognosis ( p = 0.047). These results indicated that chemotherapy could promote tumor IDO1 expression, and the increased tumor IDO1 expression after neoadjuvant therapy predicted poor pathologic response and prognosis in ESCC.

Background Stereotactic ablative radiotherapy (SABR) is the current standard‐of‐care in cases of inoperable early stage non‐small cell lung cancer (ES‐NSCLC). This study aimed to assess the survival outcomes and recurrence patterns after SABR for ES‐NSCLC in a hospital setting. Methods A single‐institution retrospective study was performed which included 109 patients who had undergone SABR. The main study endpoints were overall survival (OS), cancer specific survival (CSS), local recurrence‐free survival (LRFS), regional recurrence free survival (RRFS) and distant metastasis‐free survival (DMFS). Univariate and multivariate analysis were conducted to explore the potential factors which might be related to patient survival. Results A total of 109 patients were enrolled into the study. Median follow‐up was 44 months (range: 2–93 months). (i) Recurrence results: Among 45 patients with recurrence, 30 patients (28%) had distant metastasis (DM), 17 patients (16%) had local recurrence (LR), 10 patients (9%) had regional recurrence (RR) of lymph nodes and two patients (2%) had second primary lung cancer (SPLC). (ii) Survival results: Median OS, CSS, PFS was 78 months, 78 and 40 months. Two‐year OS, CSS, PFS, LRFS, RRFS and DMFS was 84.7%, 87.1%, 69.2%, 86.8%, 92.7% and 78.0%, respectively. Four‐year OS, CSS, PFS, LRFS, RRFS and DMFS was 55.6%, 60.7%, 37.3%, 76.3%, 88.4% and 59.4%, respectively. (iii) Univariate and multivariate analyses indicated that age was a prognostic factor of CSS in patients aged <75 years (P = 0.04 HR 2.12 95% confidence interval [CI]: 1.04–4.33). Conclusions Although high survival rates can be achieved in ES‐NSCLC patients treated with SABR, using SABR on its own may not be enough. Prolonged surveillance and adjuvant therapy is therefore needed.

BackgroundThis meta‐analysis was performed to clarify the prognostic role of the expression of T‐cell immunoglobulin mucin‐3 (TIM‐3) in different cancer types.MethodsRelated articles were searched from PubMed, EMBASE, Web of Science up to December 31, 2019. Pooled hazard ratios (HRs) and 95% confidence intervals (CIs) were utilized to explore their associations. In addition, we conducted subgroup analyses stratified by various factors.ResultsEventually, a total of 33 studies including 4223 patients were enrolled in this study. Results showed that patients with high TIM‐3 expression had shorter overall survival (OS) (HR = 1.67, 95% CI: 1.37‐2.04) and progression‐free survival (HR = 1.80, 95% CI: 1.14‐2.83), but subgroup analyses indicated there were no relationship between TIM‐3 expression and disease‐free survival or recurrence‐free survival. It was reassuring that high TIM‐3 expression may be associated with poor prognosis in osteosarcoma, gastric cancer, liver cancer, esophageal cancer, and lymphoma, while no prognostic significance was detected of TIM‐3 expression in lung cancer, kidney cancer, or breast cancer. Furthermore, we did not find association of TIM‐3 with any clinicopathological parameters.ConclusionsHigh TIM‐3 expression might be a potential biomarker which can be used to predict the poor prognosis of different cancer types, especially osteosarcoma, gastric cancer, liver cancer, esophageal cancer, and lymphoma.