Epithelial-mesenchymal transition-converted tumor cells can induce T-cell apoptosis through upregulation of programmed death ligand 1 expression in esophageal squamous cell carcinoma

Esophageal squamous cell carcinoma (ESCC) is an aggressive tumor, and it is urgently needed to develop novel therapeutic strategies including immunotherapy. In this study, we investigated the upregulation of the programmed death ligand 1 (PD-L1) due to epithelial-mesenchymal transition (EMT) in ESCC using an in vitro treatment system with the EMT inducer, glycogen synthase kinase (GSK)-3 inhibitor, and we also analyzed the correlation of EMT and PD-L1 expression in the clinical tumor samples of both tissue microarray (TMA) samples (n = 177) and whole tissue samples (n = 21). As a result, the inhibition of GSK-3β induces EMT phenotype with upregulated vimentin and downregulated E-cadherin as well as increased Snail and Zinc finger E box-binding homeobox (ZEB)-1 gene expression. Simultaneously, we showed that EMT-converted ESCC indicated the upregulation of PD-L1 at both protein (total and surface) and mRNA levels. Of importance, we showed that EMT-converted tumor cells have a capability to induce T-cell apoptosis to a greater extent in comparison to original epithelial type tumor cells. Furthermore, the immunohistochemical stains of ESCC showed that PD-L1 expression on tumor cells was positively correlated with EMT status in TMA samples (P = .0004) and whole tissue samples (P = .0029). In conclusion, our in vitro and in vivo study clearly demonstrated that PD-L1 expression was upregulated in mesenchymal type tumors of ESCC. These findings provide a strong rationale for the clinical use of anti-PD- 1/ anti-PD- L1 monoclonal antibodies for advanced ESCC patients

Anti‐PD‐1 monoclonal antibody‐resistant esophageal squamous cell carcinoma showing the abscopal effect: A case report with T‐cell receptor/B‐cell receptor repertoire analysis

Abstract Background Several clinical trials of nivolumab have reported good results, including those in patients with advanced esophageal squamous cell carcinoma. However, the response rate of this drug remains poor. Notably, a rare phenomenon called abscopal effect refers to the regression of irradiated and nonirradiated distant tumors after local radiotherapy. Although the mechanism of this effect remains unclear, the antitumor immunity induced by radiotherapy is considered to be the most important factor. Case A 66‐year‐old man with recurrent nivolumab‐resistant esophageal squamous cell carcinoma along with left‐side cervical and abdominal para‐aortic lymph node metastases was treated with a 40 Gy (10 fractions) dose of radiotherapy to the left‐side cervical lymph node metastasis as a palliative treatment, which caused neck pain. In addition, nivolumab administration was resumed the day after completion of radiotherapy. Three months after radiotherapy, the irradiated lesion on the left neck had regressed to a scar‐like lesion. Furthermore, the previously progressive abdominal para‐aortic lymph nodes outside the irradiation area shrank (abscopal effect). T‐cell receptor and B‐cell receptor (TCR/BCR) repertoire analyses before and after radiotherapy revealed that radiotherapy led to changes in the TCR/BCR repertoire. Conclusion Changes in the TCR/BCR repertoire may be a part of the mechanism underlying the abscopal effect. The findings of the present case suggest that the combination of immune checkpoint inhibitors and radiotherapy is a promising treatment approach even for patients with immune checkpoint inhibitor‐resistant cancer

Tumor-specific CD8-positive T cell-mediated antitumor immunity is implicated in the antitumor effect of local hyperthermia.

This study aimed to elucidate the contribution of T cell-mediated antitumor immunity in the antitumor effect of local hyperthermia (LH)

Combined inhibition of PD-1/PD-L1, Lag-3, and Tim-3 axes augments antitumor immunity in gastric cancer–T cell coculture models

10.1007/s10120-020-01151-8Gastric Cancer243611-62

Combination Therapy of Intravenously Injected Microglia and Radiation Therapy Prolongs Survival in a Rat Model of Spontaneous Malignant Glioma.

The aim of this study was to investigate the efficacy of combination therapy with intravenously injected microglia (MI) and radiation therapy (RT) for malignant glioma in rats

Tn Antigen Expression Defines an Immune Cold Subset of Mismatch-Repair Deficient Colorectal Cancer

Colorectal cancer (CRC) cells often express Tn antigen, a tumor-associated truncated immature O-glycan (GalNAcα-O-Ser/Thr) that can promote tumor progression. Immunotherapies against Tn antigen have been developed and are being evaluated in clinical trials. Tn antigen can also be considered a novel immune checkpoint that induces immunosuppressive signaling through glycan-biding lectins to lead effector T cell apoptosis. We evaluated the correlation of Tn antigen expression by immunohistochemistry with mismatch-repair (MMR) status, tumor-infiltrating lymphocytes, tumor cell PD-L1 expression, and clinicopathological characteristics in 507 CRC patients. Although 91.9% of CRCs showed negative or weak Tn antigen staining (Tn-negative/weak), we identified a small subset of CRCs (8.1%) that displayed particularly intense and diffuse distribution of Tn antigen immunoreactivity (Tn-strong) that closely related to deficient MMR (dMMR). Moreover, 40 dMMR CRCs were stratified into 24 Tn-negative/weak dMMR tumors (60.0%) exhibiting dense CD8+ lymphocyte infiltrate concomitant with a high rate of PD-L1 positivity, and 16 Tn-strong dMMR tumors (40.0%) that demonstrated CD8+ T cell exclusion and a lack of PD-L1 expression, which was comparable to those of proficient MMR. Our finding suggests that the immune cold subset of patients with Tn-strong dMMR CRC may be effectively treated with immune checkpoint blockade therapy or cellular immunotherapy targeting Tn antigen

Phase I/II clinical trial of nivolumab in combination with oligo-fractionated irradiation for unresectable advanced or recurrent gastric cancer

Abstract Background Although immune checkpoint inhibitors (ICI) targeting for PD-1 axis is a promising approach for advanced gastric cancer (GC) patients, the response rate is still limited. Induction of synergistic effect of irradiation with ICI targeting for the PD-1 axis can be an attractive strategy. The aim of this study was to assess the effect of the combination of irradiation with anti-PD-1 therapy for advanced GC. Methods We conducted a single-arm, phase I/II trial in GC patients treated with a combination of nivolumab and oligo-fractionated irradiation (22.5 Gy/5 fractions/5 days) (NCT03453164). Eligible patients (n = 40) had unresectable advanced or recurrent GC which progressed after primary and secondary chemotherapy with more than one lesion. The primary endpoint is the disease control rate (DCR) of non-irradiated target lesions and the secondary endpoints are the median survival time (MST), safety, and DCR of irradiated lesions. Results We observe that the DCR for the non-irradiated target as the abscopal effect is 22.5% (90% confidence interval (CI), 12.3–36.0), and the DCR for the irradiated lesion is 40.0% (90% CI, 26.9–54.2). The median survival time is 230 days (95% CI, 157–330), and grade 3 and higher adverse events (AEs) are observed in 16 patients (39 %) with no obvious additional AEs when adding irradiation. Conclusions The present study suggests that the combination of nivolumab with oligo-fractionated irradiation has the potential to induce a promising anti-tumor effect for advanced GC