BACKGROUND: Immune checkpoint inhibitors combined with chemotherapy as a neoadjuvant therapy have been applied to the treatment of esophageal squamous cell carcinoma (ESCC). However, the optimal regimen needs to be further explored, particularly for older patients, and the mechanisms by which the immune checkpoint inhibitor combined with chemotherapy modulates the evolution of ESCC are unknown.
METHODS: In this single-arm phase 2 trial, patients with resectable (stage II/III/IV without metastasis) ESCC were enrolled and received nanoparticle albumin-bound (nab) paclitaxel for two cycles and oral S-1 for 2 weeks, combined with intravenous toripalimab for two cycles before surgery. Combination postoperative adjuvant therapy was administered. The primary outcome was the major pathological response (MPR). Secondary outcomes included pathological complete response (pCR), overall response rate (ORR), disease control rate (DCR), disease-free survival (DFS), overall survival (OS), improvement in Stooler\'s dysphagia score and degree of daily living ability (dADL). Biopsies and plasma pre- and post-neoadjuvant therapy were performed using whole-exome sequencing, transcriptome sequencing, immunohistochemistry (IHC) for PD-L1, multiplex immunofluorescence (mIF) and proximity extension assay technology (PEA) for 92 proteins.
RESULTS: From November 2019 to July 2021, 60 patients were enrolled. After neoadjuvant therapy, R0 resection was achieved in 55 (98.21%) patients. MPR was identified in 27 patients (49.09%), and 16 patients (29.09%) achieved pCR. Patients with PR, SD and PD were 37 (61.67%), 21 (35.00%) and 2 (3.33%), respectively. The overall staging, Stooler dysphagia scores and dADL were significantly decreased after treatment. 11 patients (18.3%) experienced grade ≥3 AEs. Compared to PD-L1-Low patients, PD-L1-High patients had a significantly higher ratio of PR. During therapy, the tumor mutation burden (TMB) and tumor neoantigen burden (TNB) were significantly decreased in patients with PR. Differential clonal evolution within tumors was demonstrated by analysis of intratumoral heterogeneity. Transcriptome analyses revealed that the infiltration of CD4+ T lymphocytes at baseline was associated with clinical outcome. During therapy, CD8+ T cells and CD4+ T cells were increased in all patients; however, exhausted cells, nTregs and iTregs were significantly increased in patients with non-MPR. Protein analyses revealed that the levels of IFN-γ, Gal.1 and LAMP3 can predict the clinical benefit. In addition, the expression of CD83, TNFRSF4, TNFSF14, VEGFR2, ADA, ARG1, and HO-1 was associated with serious AEs. More importantly, the integration of CD4+ T cells with plasma protein of IFN-γ, Gal.1 or LAMP3 could further distinguish responders from non-responders.
CONCLUSIONS: In this study, neoadjuvant therapy with toripalimab, nab-paclitaxel and S-1 was less toxic and showed promising antitumor activity in patients with resectable ESCC. Changes in the genome, transcriptome, PD-L1 expression and serum proteins were comprehensively analyzed and correlated with clinical outcomes, which provides insight into the mechanism of action of toripalimab combined with nab-paclitaxel and S-1 in patients with ESCC.
BACKGROUND: This study was funded by Major projects of the ministry of science and technology of the 13th five-year plan of China [grant number: 2018ZX09201013].

BACKGROUND: Heart failure (HF) secondary to acute myocardial infarction (AMI) is still a worldwide problem with a high mortality rate. The current study aimed to explore early and reliable predictive biomarkers of HF following AMI.
METHODS: The gene expression profile GSE59867 was downloaded from GEO. Array data from peripheral blood mononuclear cells (PBMCs) was used from 46 control patients and 111 patients with AMI at four time points: (i) first day of AMI; (ii) 4-6 days after AMI; (iii) one month after AMI; and (iv) six months after AMI. Among the 111 AMI patients, nine with HF and eight without HF were studied. CIBERSORT was used to analyze the relative proportions of immune cells in PBMCs. The proportions of immune cells in different groups were compared. Differentially expressed genes (DEGs) were analyzed with R language packages.
RESULTS: The percentages of monocytes and neutrophils increased significantly on the first day of AMI, and then decreased gradually. The percentage of regulatory T cells increased significantly 4-6 days after AMI, while the percentage of resting memory CD4 cells, CD8 T cells, and resting natural killer cells decreased significantly on the first day of AMI, and then increased gradually. Patients who developed HF had a significantly higher proportion of neutrophils in PBMCs on the first day of AMI, but had a significantly lower proportion of naive CD4 T cells. Two shared genes, interleukin-1 receptor 2 (IL1R2) and leucine-rich repeat neuronal protein 3 (LRRN3), were found to have potentially important roles in predicting the development of HF following AMI.
CONCLUSIONS: A higher proportion of neutrophils and a lower proportion of naive CD4 T cells in PBMCs on the first day of AMI may be correlated with the development of HF following AMI. IL1R2 and LRRN3 may exert functions in the development of HF following AMI.

UNASSIGNED: Novel coronavirus disease (COVID-19) has spread globally and caused over 3 million deaths, posing great challenge on public health and medical systems. Limited data are available predictive factors for disease progression. We aim to assess clinical and radiological predictors for pulmonary aggravation in severe and critically ill COVID-19 patients.
UNASSIGNED: Patients with confirmed COVID-19 in Renmin Hospital of Wuhan University, China, between Feb. 6th, 2020 and Feb. 21st, 2020 were retrospectively collected. Enrolled patients were divided into non-progression group and progression group based on initial and follow-up chest CTs. Clinical, laboratory, and radiological variables were analyzed.
UNASSIGNED: During the study period, 162 patients were identified and a total of 126 patients, including 97 (77.0%) severe cases and 29 (23.0%) critically ill cases were included in the final analysis. Median age was 66.0 (IQR, 56.0-71.3) years. Median time from onset to initial chest CT was 15.0 (IQR, 12.0-20.0) days and median interval to follow-up was 7.0 (IQR, 5.0-7.0) days. Compared with those who did not progress (n=111, 88.1%), patients in the progression group (n=15, 11.9%) had significantly higher percentage of peak body temperature >38 °C (P=0.002), lower platelet count (P=0.011), lower CD4 T cell count (P=0.002), lower CD8 count (P=0.011), higher creatine kinase level (P=0.002), and lower glomerular filtration rate (P=0.018). On both univariate and multivariable analysis, only CD4 T cell count <200/µL was significant (OR, 6.804; 95% CI, 1.450-31.934; P=0.015) for predicting pulmonary progression.
UNASSIGNED: Low CD4 T cell count predicts progression of pulmonary change in severe and critically ill patients with COVID-19.

To describe the clinical characteristics and factors associated with CD4 T-cell count and CD4/CD8 ratio restoration in HIV mono-infected and HIV/HBV co-infected individuals, and to explore liver and renal functional changes in both groups.
A retrospective cohort study was performed including 356 HIV/HBV co-infected and 716 HIV mono-infected participants who initiated antiretroviral therapy (ART) during 2013-2017 in Beijing Youan Hospital, China. Demographic and clinical characteristics were compared between the two groups, using χ2 and Mann-Whitney non-parametric tests. Bivariate and multivariate Cox regression models were used to test their association.
Baseline HIV viral load and ART regimen were found to be significantly associated with CD4 T-cell restoration among HIV-infected participants, whereas baseline HIV viral load was the only significant factor associated with CD4 T-cell restoration in HIV/HBV co-infected participants. The final model showed that baseline HIV viral load and ART regimen were significantly associated with CD4/CD8 ratio restoration among HIV-infected participants, while baseline HIV viral load was the significant factor. Liver and renal functions were similar at the endpoint (P > 0.05).
Baseline HIV viral load count was found to be the key factor affecting immune restoration in both HIV and HIV/HBV individuals. Future multi-wave prospective studies are needed to clarify the potential biological mechanism.

Post-transplant cytomegalovirus (CMV) infections and increased viral replication are associated with CMV-specific T-cell anergy. In the ATHENA-study, de-novo everolimus (EVR) with reduced-exposure tacrolimus (TAC) or cyclosporine (CyA) showed significant benefit in preventing CMV infections in renal transplant recipients as compared to standard TAC + mycophenolic acid (MPA). However, immunomodulatory mechanisms for this effect remain largely unknown. Ninety patients from the ATHENA-study completing the 12-month visit on-treatment (EVR + TAC n = 28; EVR + CyA n = 19; MPA + TAC n = 43) were included in a posthoc analysis. Total lymphocyte subpopulations were quantified. CMV-specific CD4 T cells were determined after stimulation with CMV-antigen, and cytokine-profiles and various T-cell anergy markers were analyzed using flow cytometry. While 25.6% of MPA + TAC-treated patients had CMV-infections, no such events were reported in EVR-treated patients. Absolute numbers of lymphocyte subpopulations were comparable between arms, whereas the percentage of regulatory T cells was significantly higher with EVR + CyA versus MPA + TAC (p = 0.019). Despite similar percentages of CMV-specific T cells, their median expression of CTLA-4 and PD-1 was lower with EVR + TAC (p < 0.05 for both) or EVR + CyA (p = 0.045 for CTLA-4) compared with MPA + TAC. Moreover, mean percentages of multifunctional CMV-specific T cells were higher with EVR + TAC (27.2%) and EVR + CyA (29.4%) than with MPA + TAC (19.0%). In conclusion, EVR-treated patients retained CMV-specific T-cell functionality, which may contribute to enhanced protection against CMV infections.

BACKGROUND: Prevention of infectious diseases in the elderly is essential to establish healthy aging. Yet, immunological aging impairs successful vaccination of the elderly. Predictive biomarkers for vaccine responsiveness in middle-aged adults may help to identify responders and non-responders before reaching old age. Therefore, we aimed to determine biomarkers associated with low and high responsiveness toward a primary vaccination in middle-aged adults, for which a tetravalent meningococcal vaccine was used as a model.
METHODS: Middle-aged adults (50-65 years of age, N = 100), receiving a tetravalent meningococcal vaccination, were divided into low and high responders using the functional antibody titers at 28 days postvaccination. A total of 48 parameters, including absolute numbers of immune cells and serum levels of cytokines and biochemical markers, were determined prevaccination in all participants. Heat maps and multivariate redundancy analysis (RDA) were used to reveal immune phenotype characteristics and associations of the low and high responders.
RESULTS: Several significant differences in prevaccination immune markers were observed between the low and high vaccine responders. Moreover, RDA analysis revealed a significant association between the prevaccination immune phenotype and vaccine responsiveness. In particular, our analysis pointed at high numbers of CD4 T cells, especially naïve CD4 and regulatory T subsets, to be associated with low vaccine responsiveness. In addition, low responders showed lower prevaccination IL-1Ra levels than high responders.
CONCLUSIONS: This explorative biomarker study shows associations between the prevaccination immune phenotype and vaccine responsiveness after a primary meningococcal vaccination in middle-aged adults. Consequently, these results provide a basis for predictive biomarker discovery for vaccine responsiveness that will require validation in larger cohort studies.

OBJECTIVE: Early treatment of HIV-infected children and adults is important for optimal immune reconstitution. Infants\' immune systems are more plastic and dynamic than older children\'s or adults\', and deserve particular attention. This study aimed to understand the response of the HIV-infected infant immune system to early antiretroviral therapy (ART) and planned ART interruption and restart.
METHODS: Data from HIV-infected children enrolled the CHER trial, starting ART aged between 6 and 12 weeks, were used to explore the effect of ART on immune reconstitution. We used linear and non-linear regression and mixed-effects models to describe children\'s CD4 trajectories and to identify predictors of CD4 count during early and interrupted ART.
RESULTS: Early treatment arrested the decline in CD4 count but did not fully restore it to the levels observed in HIV-uninfected children. Treatment interruption at 40 or 96 weeks resulted in a rapid decline in CD4 T-cells, which on retreatment returned to levels observed before interruption. Naïve CD4 T-cell count was an important determinant of overall CD4 levels. A strong correlation was observed between thymic output and the stable CD4 count both before and after treatment interruption.
CONCLUSIONS: Early identification and treatment of HIV-infected infants is important to stabilize CD4 counts at the highest levels possible. Once stabilized, children\'s CD4 counts appear resilient, with good potential for recovery following treatment interruption. The naïve T-cell pool and thymic production of naive cells are key determinants of children\'s CD4 levels.

In perinatally HIV-1-infected youths living in France, we previously reported that Gag-specific CD4 and CD8 T cell proliferation is more frequently detected in patients of black ethnicity than in those of other ethnicities. We observed that black patients had higher levels of dendritic cells (DCs) than other patients. We aimed at studying the association of DC levels with Gag-specific T cell proliferation. The ANRS-EP38-IMMIP study is an observational study of youths aged between 15 and 24 years who were perinatally infected with HIV. A single blood sample was drawn for virological and immunological assays. Data from cART-treated 53 youths with undetectable plasma HIV RNA were analyzed. Gag-specific T cell proliferation was assessed by using a CFSE-based test. Peripheral blood myeloid dendritic cells (mDCs) and plasmacytoid dendritic cells (pDCs) were phenotyped by flow cytometry. Plasma markers were quantified by ELISA or multiplex assays. Logistic regression was used for univariate and multivariate analyses. Patients with Gag-specific CD4 T cell proliferative responses had significantly higher percentages and absolute counts of mDCs and pDCs in the peripheral blood than nonresponding patients. Gag-specific CD4 and CD8 T cell proliferation was associated with lower plasma sCD14 levels. Plasma levels of IFN-α, TRAIL, and chemokines involved in T cell migration to secondary lymphoid organs were not associated with T cell proliferation. Multivariate analysis confirmed the association between Gag-specific CD4 T cell proliferation and pDC levels. In conclusion, DC levels are a robust correlate of the presence of Gag-specific T cell proliferation in successfully treated youths.

This study was to investigate the differences of lymphocyte in the cerebrospinal fluid (CSF) of patients with syphilis meningitis (SM) and tuberculous meningitis (TBM) for new diagnostic insights. Totally, 79 cases of SM and 45 cases of TBM were enrolled. In the CSF, the CD4, CD45RO or CD20 positive lymphocytes were detected by immunohistochemistry. The proportion of CD4 T cells in the CSF lymphocytes in patients with SM was significantly higher than that in patients with TBM (p < 0.05). After medical therapy, there was a significantly decline trend of the CD4 T-cell proportion in both groups (p < 0.05). The proportion of CD45RO T cells in CSF lymphocytes of patients with SM was less than that of patients with TBM (p < 0.05). After medical therapy, the positive ratio of CD45RO T cells was increased in the CSF of both group patients (p < 0.05). The proportion of CD20B cells in the CSF lymphocytes was not obviously different between the two groups during every stage. In conclusion, there are strong differences of CD4 and CD45RO T-cell ratio, but not the CD20 B cells in the meningitis. CD4 and CD45RO T cells in CSF are a useful complement in differentially diagnosing SM and TBM; it contributes to further understand the pathogenesis and prognosis of SM and TBM.

OBJECTIVE: To study the effect and mechanism of the dysfunction of CD4(+) T cells in the disease process of chronic cardiac failure (CHF).
METHODS: According to different group technologies, 100 CHF patients were divided into the following groups: ischemia group and non-ischemia group, heart function Ⅲ-Ⅳ group and heart function Ⅰ-Ⅱ group, event group and non-event group, and 50 healthy volunteers were included in the control group. Real-time PCR was used to detect transcription factors T-bet and GATA-3 of Th1 and Th2; flow cytometry was applied to determine the ratio of Th17 and Treg cells; ELISA was employed to test cytokines IFN-γ, IL-4, IL-17 and IL-10 of peripheral blood Th1, Th2, Th17 and Treg cells, respectively; ultrasonic cardiogram was used to exploit to LVEF and LVEDd; and electrochemilu minescene immunoassay was used to examine plasma BNP. The differences of all indexes of all groups were analyzed and the correlation between CD4 T cells and clinical indexes was analyzed by Pearson correlation analysis.
RESULTS: As compared to the control group, the transcription factors T-bet and GATA-3 of Th1 and Th2, the ratio of cytokines Th17 and IFN-γ, cytokines IL-17, T-bet/GATA-3, IFN-γ/IL-4, Th17 cells/Treg cells, IL-17/IL-10 of the ischemia group and non-ischemia group, heart function Ⅲ-Ⅳ group and heart function Ⅰ-Ⅱ group, event group and non-event group were all increased significantly, while their transcription factor GATA-3 of Th2, cytokines IL-4, Treg cells ratio, cytokines IL-10 were decreased obviously. The differences showed statistical significance (P < 0.05). The increase or decrease of the partial CD4+ T cells of the ischemia group, heart function Ⅲ-Ⅳ group and event group was more distinctly. The results of Pearson correlation analysis showed that IFN-γ and IL-17 were significantly positively correlated with LVEDd and BNP, IL-4 and IL-10 were also significantly positively correlated with LVEF, but correlated negatively with BNP, and IL-17 was negatively correlative with LVEF.
CONCLUSIONS: There was a correlation between CHF and the dysfunction of CD4(+) T cells showing immune activation phenomenons of deviations from the Th1/Th2 balance towards Th1 and from the Th17/Treg balance towards Th17, which was also related to the types, severity and prognosis of the disease.