BackgroundBlocking the programmed death protein 1 (PD-1)/programmed death-ligand 1 (PD-L1) pathway in hepatocellular carcinoma (HCC) is a very promising approach in immunotherapy. However, the correlation and prognostic values of serum soluble PD-1 and PD-L1 (sPD-1/sPD-L1) have not been explored conjointly in HCC patients.MethodsThis study retrospectively included 120 HCC patients receiving radical resection. The serum levels of sPD-1/sPD-L1 and inflammatory cytokines were measured by antibody array assay. Immunohistochemistry was applied to assess both the expression of membrane-bound PD-L1, and the number of CD4+ tumor-infiltrating lymphocytes (TILs) and CD8+ TILs.ResultsThe best cut-off values of sPD-1 and sPD-L1 for predicting disease-free survival (DFS) were 33.0 µg/ml and 11.2 µg/ml, respectively. Multivariable analysis showed that sPD-L1 was a negative independent prognostic factor [DFS, Hazard Ratio (HR) 2.58, 95% CI 1.14–5.84, P = 0.023; overall survival (OS), HR 1.77, 95% CI 1.01–3.12, P = 0.048], while sPD-1 was a favorable independent prognostic factor (DFS, HR 0.32, 95% CI 0.14–0.74, P = 0.007; OS, HR 0.54, 95% CI 0.30–0.98, P = 0.044) in HCC patients. We also observed some similar associations between inflammatory cytokines (IL-10, IL-17, TNF-α) and sPD-1 or sPD-L1, as well as a close positive association between sPD-1 and sPD-L1. No significant associations of sPD-1/sPD-L1 with either intra-tumoral PD-L1 expression, or the numbers of CD4+ TILs and CD8+ TILs were determined.ConclusionsOur findings indicate that sPD-1 and sPD-L1 are independent prognostic factors with opposite prognostic roles in predicting both DFS and OS in HCC patients.Electronic supplementary materialThe online version of this article (10.1007/s00262-018-2271-4) contains supplementary material, which is available to authorized users.
The potential for the use of contrast echocardiography to study myocardial perfusion has generated efforts to develop standardized echo contrast agents. The two methods used in this laboratory to generate microbubbles in solutions serving as contrast agents included the widely used hand-agitation method and the newer ultrasonic microcavitation (sonication) method. The latter has been demonstrated to generate smaller and more uniform microbubbles in an in vitro system. The present study was designed to observe, by direct microscopic examination of a cat mesentery preparation, the behavior and fate of the microbubbles in an in vivo system. The in vivo mesentery observations confirm the critical role of microbubble size in its unhindered passage through the capillary vasculature. The smaller and more uniform sonicated microbubbles passed rapidly through the microcirculation along with the red blood cells, whereas the larger microbubbles were observed to coalesce and interrupt the flow of blood and subsequently collapse or shrink.
Purpose: To establish a useful prognostic nomogram to predict long-term overall survival for patients with tongue squamous cell carcinoma (TSCC) after R0 resection.Patients and Methods: The nomogram was developed using a retrospective cohort of 235 TSCC patients from Sun Yat-sen University Cancer Center between 1 January 2000 and 31 December 2007. An independent dataset of 223 patients was used for external validation. Multivariate Cox proportional hazards model (backward selection; the Akaike information criteria) was applied to select variables for construction of the nomogram. Discrimination and calibration were performed using the area under the receiver operating characteristic (ROC) curve (AUC) and calibration plots.Results: Using the backward selection of clinically-relevant variables, depth of invasion (hazard ratio [HR], 3.55; P < 0.001), pN (HR, 3.48; P = 0.01), age (HR, 1.03; P < 0.01) and neck dissection (HR, 0.53; P = 0.04) were selected as independent predictive factors of survival. A nomogram was thus established to predict survival of TSCC patients after R0 resection. The calibration curve demonstrated that the nomogram was able to accurately predict 5-year overall survival (OS). In addition, our data showed the AUC of the nomogram were 0.78 and 0.71 based on the internal and external validation, which were significantly better than the 7th TNM stage (0.64/0.55).Conclusion: The proposed nomogram resulted in accurate prognostic prediction of the 5-year OS for TSCC patients with R0 resection.
STING, an endoplasmic reticulum (ER) transmembrane protein, mediates innate immune activation upon cGAMP stimulation and is degraded through autophagy. Here, we report that activated STING could be transferred between cells to promote antitumor immunity, a process triggered by RAB22A-mediated non-canonical autophagy. Mechanistically, RAB22A engages PI4K2A to generate PI4P that recruits the Atg12–Atg5–Atg16L1 complex, inducing the formation of ER-derived RAB22A-mediated non-canonical autophagosome, in which STING activated by agonists or chemoradiotherapy is packaged. This RAB22A-induced autophagosome fuses with RAB22A-positive early endosome, generating a new organelle that we name Rafeesome (RAB22A-mediated non-canonical autophagosome fused with early endosome). Meanwhile, RAB22A inactivates RAB7 to suppress the fusion of Rafeesome with lysosome, thereby enabling the secretion of the inner vesicle of the autophagosome bearing activated STING as a new type of extracellular vesicle that we define as R-EV (RAB22A-induced extracellular vesicle). Activated STING-containing R-EVs induce IFNβ release from recipient cells to the tumor microenvironment, promoting antitumor immunity. Consistently, RAB22A enhances the antitumor effect of the STING agonist diABZI in mice, and a high RAB22A level predicts good survival in nasopharyngeal cancer patients treated with chemoradiotherapy. Our findings reveal that Rafeesome regulates the intercellular transfer of activated STING to trigger and spread antitumor immunity, and that the inner vesicle of non-canonical autophagosome originated from ER is secreted as R-EV, providing a new perspective for understanding the intercellular communication of organelle membrane proteins.
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