No abstract

BackgroundRecent impressive advances in cancer immunotherapy have been largely derived from cellular immunity. The role of humoral immunity in carcinogenesis has been less understood. Based on our previous observations we hypothesize that an immunoglobulin subtype IgG4 plays an essential role in cancer immune evasion.MethodsThe distribution, abundance, actions, properties and possible mechanisms of IgG4 were investigated with human cancer samples and animal tumor models with an extensive array of techniques both in vitro and in vivo.ResultsIn a cohort of patients with esophageal cancer we found that IgG4-containing B lymphocytes and IgG4 concentration were significantly increased in cancer tissue and IgG4 concentrations increased in serum of patients with cancer. Both were positively related to increased cancer malignancy and poor prognoses, that is, more IgG4 appeared to associate with more aggressive cancer growth. We further found that IgG4, regardless of its antigen specificity, inhibited the classic immune reactions of antibody-dependent cell-mediated cytotoxicity, antibody-dependent cellular phagocytosis and complement-dependent cytotoxicity against cancer cells in vitro, and these effects were obtained through its Fc fragment reacting to the Fc fragments of cancer-specific IgG1 that has been bound to cancer antigens. We also found that IgG4 competed with IgG1 in reacting to Fc receptors of immune effector cells. Therefore, locally increased IgG4 in cancer microenvironment should inhibit antibody-mediated anticancer responses and help cancer to evade local immune attack and indirectly promote cancer growth. This hypothesis was verified in three different immune potent mouse models. We found that local application of IgG4 significantly accelerated growth of inoculated breast and colorectal cancers and carcinogen-induced skin papilloma. We also tested the antibody drug for cancer immunotherapy nivolumab, which was IgG4 in nature with a stabilizing S228P mutation, and found that it significantly promoted cancer growth in mice. This may provide an explanation to the newly appeared hyperprogressive disease sometimes associated with cancer immunotherapy.ConclusionThere appears to be a previously unrecognized immune evasion mechanism with IgG4 playing an essential role in cancer microenvironment with implications in cancer diagnosis and immunotherapy.

Primary esophageal MEC is a rare disease and prone to be misdiagnosed. Lymph node metastasis and operation are independent prognostic factors. Surgical resection is the primary treatment, but the prognosis is poor.

Nuclear receptor coactivator 1 (NCOA1) plays crucial roles in the regulation of gene expression mediated by a wide spectrum of steroid receptors such as androgen receptor (AR), estrogen receptor α (ER α), and estrogen receptor β (ER β). Therefore, dysregulations of NCOA1 have been found in a variety of cancer types. However, the clinical relevance and the functional roles of NCOA1 in human esophageal squamous cell carcinoma (ESCC) are less known. We found in this study that elevated levels of NCOA1 protein and/or mRNA as well as amplification of the NCOA1 gene occur in human ESCC. Elevated levels of NCOA1 due to these dysregulations were not only associated with more aggressive clinic‐pathologic parameters but also poorer survival. Results from multiple cohorts of ESCC patients strongly suggest that the levels of NCOA1 could serve as an independent predictor of overall survival. In addition, silencing NCOA1 in ESCC cells remarkably decreased proliferation, migration, and invasion. These findings not only indicate that NCOA1 plays important roles in human ESCC but the levels of NCOA1 also could serve as a potential prognostic biomarker of ESCC and targeting NCOA1 could be an efficacious strategy in ESCC treatment.

Background Emerging evidences suggest that lymph node ratio (LNR), the number of metastatic lymph node (LN) to the total number of dissected lymph nodes (NDLN), may predict survival in multiple types of solid tumor. However, the prognostic role of LNR in adenocarcinoma of the esophagogastric junction (AEG) remains uninvestigated. The study is intended to determine the prognostic value of LNR in the patients with Siewert type II AEG. Methods A total of 342 patients with Siewert type II AEG who underwent R0 resection were enrolled in this study. The optimal cutoff of LNR was strati ed into tertiles using X-tile software. The log-rank test was used to evaluate the survival differences, and multivariate Cox regression analysis were performed to determine the independent prognostic variables. Results The optimal cutoff of LNR were classi ed as LNR = 0, LNR between 0.01 and 0.40 and LNR > 0.41. Patients with high LNR had a shorter 5-and 10-year disease-speci c survival (DSS) rate (8.5%, 1.4%) compared with those with moderate LNR (20.4%, 4.9%) and low LNR (58.0%, 27.5%) (P < 0.001). Multivariate Cox regression analysis indicated that LNR was an independent factor for DSS after adjusting for confounding variables (P < 0.05). Furthermore, after strati cation by NDLN between NDLN < 15 group and NDLN ≥ 15 group, the LNR remained a signi cant predictor for DSS (P < 0.05). Conclusions LNR is an independent predictor for DSS in patients with Siewert type II AEG regardless of NDLN. Patients with higher LNR have signi cantly shorter DSS.