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BackgroundRecently, a few researches focus on the correlation between postoperative carcinoembryonic antigen (post-CEA) and the outcome of colorectal cancer (CRC), but none investigates the predictive value of post-CEA in a prognostic model. Besides, current recommendations on the frequency of post-CEA surveillance are not individualized and well followed. There is an absence of identification of patients who are more likely to have abnormal post-CEA levels and need more frequent CEA measurements.MethodsConsecutive CRC patients who underwent curative surgery were enrolled and randomly divided into the discovery (n=352) and testing cohort (n=233). Impacts of preoperative CEA (pre-CEA) and post-CEA on prognosis were assessed. Cox regression model was applied to develop prognostic nomograms, which were validated by the concordance index (C-index), calibration curve, and receiver operating characteristic curve (ROC) analysis. And prediction improvement of the nomograms was assessed with net reclassification improvement (NRI) and integrated discrimination improvement (IDI). Logistic regression was used to identify predictive risk factors and construct the prediction model for post-CEA elevation.ResultsPost-CEA independently predicted overall survival (OS) and disease-free survival (DFS), while pre-CEA did not. Post-CEA elevation represented higher risks in patients with normal pre-CEA, compared to those with persistent elevated CEA. The nomograms for OS and DFS were established with body mass index, tumor differentiation, N stage, lymphocyte-to-monocyte ratio, and post-CEA. The nomograms showed good calibration and superior discrimination than pTNM stage, with the C-index of 0.783 and 0.759 in the discovery set and 0.712 and 0.774 in the testing set for OS and DFS, respectively. Comparisons between models using IDI and NRI implied that the nomograms performed better than pTNM stage and the predictive power could be improved with the addition of post-CEA. The prediction model for post-CEA elevation was established with age, platelet-to-lymphocyte ratio, preoperative CA19-9, and pre-CEA. The AUC of the model in the two cohorts was 0.802 and 0.764, respectively.ConclusionsElevated post-CEA was a strong indicator of poor prognosis. The addition of post-CEA significantly enhanced the performance of prognostic nomograms. And the prediction model for post-CEA elevation may help identify patients who ought to reasonably receive more intensive postoperative surveillance of CEA levels.

Gastric cancer cell-derived exosomes as biomarkers have a very high application potential to the non-invasive detection of early-stage gastric cancer. However, the small size of exosomes (30–150 nm) results in huge challenges in separating and detecting them from complex media (e.g., plasma, urine, saliva, and cell culture supernatant). Here we proposed a highly integrated exosome separation and detection (ExoSD) chip to immunomagnetic separate exosomes from cell culture supernatant in a manner of continuous flow, and to immunofluorescence detect gastric cancer cell-derived exosomes with high sensitivity. The ExoSD chip has achieved a high exosome recovery (>80%) and purity (>83%) at the injection rate of 4.8 mL/h. Furthermore, experimental results based on clinical serum samples of patients with gastric cancer (stages I and II) show that the detection rate of the ExoSD chip is as high as 70%. The proposed ExoSD chip has been successfully demonstrated as a cutting-edge platform for exosomes separation and detection. It can be served as a versatile platform to extend to the applications of separation and detection of the other cell-derived exosomes or cells.

The transcription factor forkhead box P3 (FOXP3) is essential for the development of regulatory T cells (Tregs) and their function in immune homeostasis. Previous studies have shown that in natural Tregs (nTregs), FOXP3 can be regulated by polyubiquitination and deubiquitination. However, the molecular players active in this pathway, especially those modulating FOXP3 by deubiquitination in the distinct induced Treg (iTreg) lineage, remain unclear. Here, we identify the ubiquitin‐specific peptidase 44 (USP44) as a novel deubiquitinase for FOXP3. USP44 interacts with and stabilizes FOXP3 by removing K48‐linked ubiquitin modifications. Notably, TGF‐β induces USP44 expression during iTreg differentiation. USP44 co‐operates with USP7 to stabilize and deubiquitinate FOXP3. Tregs genetically lacking USP44 are less effective than their wild‐type counterparts, both in vitro and in multiple in vivo models of inflammatory disease and cancer. These findings suggest that USP44 plays an important role in the post‐translational regulation of Treg function and is thus a potential therapeutic target for tolerance‐breaking anti‐cancer immunotherapy., The ubiquitin‐specific peptidase 44 (USP44) interacts with FOXP3 and stabilizes the transcription factor by removing K48‐linked ubiquitin modifications. USP44 is essential for the establishment of fully functional regulatory T cells.

Regulatory T (Treg) cells play central roles in maintaining immune homeostasis and self-tolerance. However, the molecular mechanisms underlying Treg cell homeostasis and suppressive function are still not fully understood. Here, we report that the deletion of another P subfamily members of the forkhead box (Foxp) subfamily member Foxp1 in Treg cells led to increased numbers of activated Treg (aTreg) cells at the expense of quiescent Treg cells, and also resulted in impaired Treg suppressive function. Mice with Foxp1-deficient Treg cells developed spontaneous inflammatory disease with age; they also had more severe inflammatory disease in colitis and experimental autoimmune encephalomyelitis (EAE) models. Mechanistically, we found that Foxp1 bound to the conserved noncoding sequence 2 (CNS2) element of the Foxp3 locus and helped maintain Treg suppressive function by stabilizing the Foxp3 expression. Furthermore, we found that Foxp1 and Foxp3 coordinated the regulation of cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) expression levels. Taken together, our study demonstrates that Foxp1 plays critical roles in both maintaining Treg cell quiescence during homeostasis and regulating Treg suppressive function., The transcription factor Foxp3 has been considered as the master regulator of regulatory T cells (Tregs), but this study shows that another Foxp subfamily member, Foxp1, plays important roles in the homeostasis, stability, and suppressor function of Tregs.

Immune memory is an important feature of adaptive immunity, which represents the capacity of our immune system to elicit faster and stronger immune responses after its re-exposure to the same antigen. Immune memory provides better protection for host against invading insults. As immune cells undertake the function of memorizing antigens by host, the generation and maintenance of memory immune cells is critical for immunological memory. Memory immune cells express a unique pattern of surface markers and they exploit different regulatory programs from naive or effector cells. Here, whether the maintenance of long-term immunologic memory requires persistent antigen stimulation remains to be an elusive topic for several decades. Currently, there are two major views on the maintenance of immunological memory. One is that immunological memory requires persistent antigenic stimulation, while the other one is that primed immune system can produce long-lived immune cells and thus do not need persistent antigen exposure. Therefore, the key question is whether memory cells have true memory capacity or they are just the consequence of immune response to persistent antigens in the pathogenic environment. As the capacity of immune system is limited, immune systems must make their choices on whether to retain the previous antigen-specific memory T cells or clear the way to make room for the proliferation of new antigen-specific T cells. Our review will mainly focus on memory T cells, in which we discussed about the dependency on antigenic stimulation as for generation and maintenance of memory T cells. We summarized the studies on antigen dependency at the transition stage from effector T cells to memory T cells. We also reviewed recent studies involving acute and chronic infection for the memory T cell maintenance. Interestingly, present studies showed that the requirement for antigen stimulation is different in acute and chronic infection, suggesting a distinct regulatory mechanism of memory T cells in these two circumstances. As for memory B cells, conventional view is that their generation and maintenance require persistent exposure to antigenic stimulation. Actually, no matter studying the requirement for persistent antigenic stimulation of memory T cells or B cells, the main challenge is how to exclude the remaining antigen present in the cellular environment. Finally, further understanding on this topic will not only provide new insights into the experimental design and clinical development of novel vaccines, but also open a new window for immunotherapy of autoimmune disease and cancer.

CD4+ CD25+ regulatory T (Treg) cells comprise a unique subset of T cells required for maintaining immune homeostasis. However, the molecular mechanisms associated with the functional variety of Treg cells are not fully delineated. In the present study, we demonstrate that ubiquitin-specific protease (USP)4 physically interacted with interferon regulatory factor 8 (IRF8) function via a K48-linked deubiquitinase, which stabilized IRF8 protein levels in Treg cells. Depletion of USP4 promoted the polyubiquitination of IRF8 and the upregulation of type 2 inflammatory cytokine gene expression in Treg cells. Consistently, treatment of Treg cells with USP4 inhibitor facilitated the polyubiquitination of IRF8. In addition, the deficiency of USP4 alleviated the suppressive function of Treg cells. Taken together, our results suggest that USP4 interacts with and stabilizes IRF8 to promote the suppressive function of Treg cells.