Integrated single-cell transcriptome and T cell receptor profiling reveals defects of T cell exhaustion in pulmonary tuberculosis.

Tuberculosis-affected lungs with chronic inflammation harbor abundant immunosuppressive immune cells but the nature of such inflammation is unclear. Dysfunction in T cell exhaustion, while implicated in chronic inflammatory diseases, remains unexplored in tuberculosis. Given that immunotherapy targeting exhaustion checkpoints exacerbates tuberculosis, we speculate that T cell exhaustion is dysfunctional in tuberculosis. Using integrated single-cell RNA sequencing and T cell receptor profiling we reported defects in exhaustion responses within inflamed tuberculosis-affected lungs. Tuberculosis lungs demonstrated significantly reduced levels of exhausted CD8+ T cells and exhibited diminished expression of exhaustion-related transcripts among clonally expanded CD4+ and CD8+ T cells. Additionally, clonal expansion of CD4+ and CD8+ T cells bearing T cell receptors specific for CMV was observed. Expanded CD8+ T cells expressed the cytolytic marker GZMK. Hence, inflamed tuberculosis-affected lungs displayed dysfunction in T cell exhaustion. Our findings likely hold implications for understanding the reactivation of tuberculosis observed in patients undergoing immunotherapy targeting the exhaustion checkpoint.

Single-cell RNA-sequencing reveals heterogeneity and intercellular crosstalk in human tuberculosis lung.

Lung inflammation indicated by 18F-labeled fluorodeoxyglucose (FDG) in patients with tuberculosis is associated with disease severity and relapse risk upon treatment completion. We revealed the heterogeneity and intercellular crosstalk in lung tissues with 18F-FDG avidity and adjacent uninvolved tissues from 6 tuberculosis patients by single-cell RNA-sequencing. Tuberculous lungs had an influx of regulatory T cells (Treg), exhausted CD8 T cells, immunosuppressive myeloid cells, conventional DC, plasmacytoid DC, and neutrophils. Immune cells in inflamed lungs showed general up-regulation of ATP synthesis and interferon-mediated signaling. Immunosuppressive myeloid and Treg cells strongly displayed transcriptions of genes related to tuberculosis disease progression. Intensive crosstalk between IL4I1-expressing myeloid cells and Treg cells involving chemokines, costimulatory molecules, and immune checkpoints, some of which are specific in 18F-FDG-avid lungs, were found. Our analysis provides insights into the transcriptomic heterogeneity and cellular crosstalk in pulmonary tuberculosis and guides unveiling cellular and molecular targets for tuberculosis therapy.

Identification of unique transcriptomic signatures and key genes through RNA sequencing and integrated WGCNA and PPI network analysis in HIV infected lung cancer.

With the widespread use of highly active antiretroviral therapy (HARRT), the survival time of AIDS patients has been greatly extended. However, the incidence of lung cancer in HIV-infected patients is increasing and has become a major problem threatening the survival of AIDS patients. The aim of this study is to use Weighted Gene Co-expression Network Analysis (WGCNA) and differential gene analysis to find possible key genes involved in HIV-infected lung cancer. In this study, using lung tissue samples from five pairs of HIV-infected lung cancer patients, second-generation sequencing was performed and transcriptomic data were obtained. A total of 132 HIV-infected lung cancer-related genes were screened out by WGCNA and differential gene expression analysis methods. Based on gene annotation analysis, these genes were mainly enriched in mitosis-related functions and pathways. In addition, in protein-protein interaction (PPI) analysis, a total of 39 hub genes were identified. Among them, five genes (ASPM, CDCA8, CENPF, CEP55, and PLK1) were present in both three hub gene lists (intersection gene, DEGs, and WCGNA module) suggesting that these five genes may become key genes involved in HIV-infected lung cancer.

Prognostic nomogram for surgery of lung cancer in HIV-infected patients.

BACKGROUND: This study aimed to establish an effective prognostic nomogram for surgery of lung cancer in HIV-infected patients. METHODS: The nomogram is based on a retrospective study of 51 patients who underwent lung cancer surgery at the Shanghai Public Health Clinical Center from July 2012 to November 2019. The predictive accuracy and discriminative ability of the nomogram were determined by concordance index (C-index) and calibration curve analysis. Internal validity was assessed using bootstrapping validation. RESULTS: Predictors contained in the prognostic nomogram included age, CD4+ cell count, surgery method, and pathological stage. The model displayed good discrimination with a C-index of 0.755 (95% CI: 0.715-0.795) and good calibration. A high C-index value of 0.844 was reached after internal validation. CONCLUSIONS: The proposed nomogram may result in more-accurate prognostic predictions for surgery of lung cancer in HIV-infected patients.

Lung cancer surgery in HIV-infected patients: An analysis of postoperative complications and long-term survival.

BACKGROUND: The purpose of this study was to investigate the risk factors of postoperative complications and reliable prognostic factors of long-term survival in HIV-infected patients with non-small cell lung cancer (NSCLC). METHODS: HIV-infected patients with NSCLC who underwent surgical treatment were retrospectively studied; a single-institutional analysis was conducted from November 2011 to August 2018. Pre- and postoperative clinical data, including age, gender, smoking history, highly active antiretroviral therapy (HAART), CD4+ T cell count, HIV viral load, cancer histology, clinical and pathological stage (p-stage), surgical result, Glasgow Prognostic Score (GPS), the Charlson comorbidity index (CCI), survival time and postoperative complications were collected. RESULTS: A total of 33 HIV-infected patients with NSCLC were enrolled of which 18 (54.7%) had preoperative comorbidities and postoperative complications were observed in 22 (66.7%) patients. Thirty-day mortality was not observed in these patients. Median survival time after surgery was 65 months: the MST of p-stage I patients was 65 months; p-stage II MST was unestimable; p-stage III MST was 21 months. Univariate analyses showed that postoperative complications were associated with HIV viral load (P = 0.002), CCI (P = 0.027), HAART (P = 0.028) and CD4+ T cell count (P = 0.045). However, multiple logistic regression analysis showed no correlation between HAART and postoperative complications. The p-stage was an independent prognostic factor for survival time. CONCLUSIONS: In our single-arm retrospective analysis, the risk factors for postoperative complications in HIV-infected patients with NSCLC were HIV viral load, CCI and CD4+ T cell counts. The p-stage was a predictive factor for long-term survival.