Dataset Information

Prognostic significance of peripheral CD8+CD28+ and CD8+CD28- T cells in advanced non-small cell lung cancer patients treated with chemo(radio)therapy.

ABSTRACT: BACKGROUND:Noninvasive prognostic biomarkers are needed for advanced non-small cell lung cancer (NSCLC) patients with different histological types to identify cases with poor survival. Here, we investigated the prognostic values of peripheral CD8+CD28+ T cells and CD8+CD28- T cells in advanced NSCLC patients treated with chemo(radio)therapy and the impact of histological type on them. METHODS:Of 232 registered advanced NSCLC patients, 101 treatment-naïve individuals were eligible and included in our study. Flow cytometry was used to evaluate CD8+CD28+ T cells, CD8+CD28- T cells, CD4+ CD25hi T cells, B cells, natural killer cells, ??T cells, and natural killer T cells in patients' peripheral blood. RESULTS:The median follow-up time was 13.6 months. Fifty-nine (58.4%) patients died by the end of our study. Fifty-three of the 101 advanced NSCLC cases selected for our study were adenocarcinomas (ADs), and 48 were squamous cell carcinomas (SCCs). Multivariate analyses showed that increased levels of CD8+CD28+ T cells independently predicted favorable overall survival (OS) [hazard ratio (HR): 0.51, 95% confidence interval (CI) 0.30-0.89, P?=?0.021] and progression-free survival (PFS) (HR: 0.66, 95% CI 0.37-0.93, P?=?0.038) in ADs, but the prediction in SCCs was not statistically significant. In contrast, high levels of CD8+CD28- T cells independently predicted unfavorable OS (HR: 1.41, 95% CI 1.17-3.06, P?=?0.035) and PFS (HR: 2.01, 95% CI 1.06-3.85, P?=?0.029) in SCCs, but the prediction in ADs was not statistically significant. ADs had higher levels of CD4+CD25hi T cells and CD8+CD28- T cells and lower NK cells (all P?

SUBMITTER: Liu C

PROVIDER: S-EPMC6796409 | biostudies-literature | 2019 Oct

REPOSITORIES: biostudies-literature

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Prognostic significance of peripheral CD8+CD28+ and CD8+CD28- T cells in advanced non-small cell lung cancer patients treated with chemo(radio)therapy.

Liu Chao C Jing Wang W An Ning N Li Aijie A Yan Weiwei W Zhu Hui H Yu Jinming J

Journal of translational medicine 20191017 1

<h4>Background</h4>Noninvasive prognostic biomarkers are needed for advanced non-small cell lung cancer (NSCLC) patients with different histological types to identify cases with poor survival. Here, we investigated the prognostic values of peripheral CD8+CD28+ T cells and CD8+CD28- T cells in advanced NSCLC patients treated with chemo(radio)therapy and the impact of histological type on them.<h4>Methods</h4>Of 232 registered advanced NSCLC patients, 101 treatment-naïve individuals were eligible ...[more]

PMID: 31623615

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Project description:Lack of reliable predictive biomarkers is a major limitation of combination therapy with chemotherapy and anti-programmed cell death protein 1/programmed death-ligand 1 (anti-PD-1/PD-L1) therapy (chemo-immunotherapy). We previously observed that the increase of peripheral blood CD8+ T cells expressing CX3CR1, a marker of differentiation, correlates with response to anti-PD-1 therapy; however, the predictive and prognostic value of T-cell CX3CR1 expression during chemo-immunotherapy is unknown. Here, we evaluated the utility of circulating CX3CR1+CD8+ T cells as a predictive correlate of response to chemo-immunotherapy in patients with non-small cell lung cancer (NSCLC). At least 10% increase of the CX3CR1+ subset in circulating CD8+ T cells from baseline (CX3CR1 score) was associated with response to chemo-immunotherapy as early as 4 weeks with 85.7% overall accuracy of predicting response at 6 weeks. Furthermore, at least 10% increase of the CX3CR1 score correlated with substantially better progression-free (P = 0.0051) and overall survival (P = 0.0138) on Kaplan-Meier analysis. Combined single-cell RNA/T-cell receptor (TCR) sequencing of circulating T cells from longitudinally obtained blood samples and TCR sequencing of tumor tissue from the same patient who received a long-term benefit from the treatment demonstrated remarkable changes in genomic and transcriptomic signatures of T cells as well as evolution of TCR clonotypes in peripheral blood containing highly frequent tumor-infiltrating lymphocyte repertoires overexpressing CX3CR1 early after initiation of the treatment despite stable findings of the imaging study. Collectively, these findings highlight the potential utility of T-cell CX3CR1 expression as a dynamic blood-based biomarker during the early course of chemo-immunotherapy and a marker to identify frequent circulating tumor-infiltrating lymphocyte repertoires.SignificanceCurrent approaches to combined chemotherapy and anti-PD-1/PD-L1 therapy (chemo-immunotherapy) for patients with NSCLC are limited by the lack of reliable predictive biomarkers. This study shows the utility of T-cell differentiation marker, CX3CR1, as an early on-treatment predictor of response and changes in genomic/transcriptomic signatures of circulating tumor-infiltrating lymphocyte repertoires in patients with NSCLC undergoing chemo-immunotherapy.

Project description:BackgroundRegulatory T cells (Treg cells) in the peripheral blood of patients with pulmonary tuberculosis (PTB) may be closely related to the progression of PTB. In this study, the distribution characteristics and clinical importance of CD8+CD28- Treg cells in patients with tuberculosis were systematically analyzed, and the role and importance of CD8+CD28- Treg cells in influencing the immune response and progression of tuberculosis were discussed, which will provide immunological indices and reference values for the clinical diagnosis of tuberculosis.MethodsFlow cytometry, sputum smears and computed tomography imaging were used to analyze the distribution characteristics of CD8+CD28- Treg cells in the peripheral blood of patients with PTB and the correlation between CD8+CD28-Treg cells and clinical and immune indices.ResultsThe percentages of CD4+CD25high and CD8+CD28- Treg cells in the peripheral blood of patients with PTB were significantly higher than those in the healthy control (HC) group. Further analysis showed that the percentage of CD4+CD25highTreg cells in the Stage II group was significantly higher than that in the HC group. The percentages of CD4+CD25high and CD8+CD28- Treg cells increased significantly in patients in the Stage II group. The proportion of CD8+CD28- Treg cells was directly proportional to the degree of positivity in sputum smears, while CD4+CD25highTreg cells did not exhibit this trend. The correlations between the percentage of CD4+CD25high and CD8+CD28- Treg cells and the percentage of lymphocyte subsets were examined. The percentage of CD8+CD28- Treg cells was negatively correlated with the percentage of CD4+T cells and positively correlated with the CD8+T cell percentage in the HC and PTB groups. The percentage of CD4 + CD25highTreg cells was positively correlated with the percentage of CD4+T cells only in the PTB group.ConclusionsThis study was the first to show that the proportion of CD8+CD28- Treg cells in the peripheral blood of patients with PTB was significantly increased, and the increase in CD8+CD28- Treg cells was related to the progression of PTB, which may affect the proportion of immune cell subsets by inhibiting the immune response, resulting in the progression of PTB.

Project description:BackgroundImmune checkpoint blockade (ICB) has significantly prolonged survival of non-small cell lung cancer (NSCLC) patients, although most patients develop mechanisms of resistance. Recently single-cell RNA-sequencing (scRNA-Seq) revealed a huge T-cell phenotypic and (dys)functional state variability. Accordingly, T-cell exhaustion is recognized as a functional adaptation, with a dynamic progression from a long-lived "pre-exhausted stem-like progenitor" to a "terminally exhausted" state. In this scenario it is crucial to understand the complex interplay between co-stimulatory and inhibitory molecules in CD8+ T-cell functionality.MethodsTo gain a baseline landscape of the composition, functional states, and transcriptomic signatures predictive of prognosis, we analyzed CD8+ T-cell subsets characterized by the presence/absence of PD1 and CD28 from periphery, adjacent non-tumor tissue and tumor site of a cohort of treatment-naïve NSCLC patients, by integrated multiparametric flow cytometry, targeted multi-omic scRNA-seq analyses, and computational pipelines.ResultsDespite the increased PD1 levels, an improved PD1+CD28+ T-cell polyfunctionality was observed with the transition from periphery to tumor site, associated with lack of TIGIT, TIM-3 and LAG-3, but not with Ag-experienced-marker CD11a. Differently from CD28+ T cells, the increased PD1 levels in the tumor were associated with reduced functionality in PD1+CD28- T cells. CD11ahigh, although expressed only in a small fraction of this subset, still sustained its functionality. Absence of TIGIT, TIM-3 and CTLA-4, alone or combined, was beneficial to CD28- T cells. Notably, we observed distinct TRM phenotypes in the different districts, with CD28+ T cells more capable of producing TGFβ in the periphery, potentially contributing to elevated CD103 levels. In contrast CD28- TRM mainly produced CXCL13 within the tumor. ScRNA-seq revealed 5 different clusters for each of the two subsets, with distinctive transcriptional profiles in the three districts. By interrogating the TCGA dataset of patients with lung adenocarcinoma (LUAD) and metastatic NSCLC treated with atezolizumab, we found signatures of heterogeneous TRM and "pre-exhausted" long-lived effector memory CD8+ T cells associated with improved response to ICB only in the presence of CD28.ConclusionsOur findings identify signatures able to stratify survival of LUAD patients and predict ICB response in advanced NSCLC. CD28 is advocated as a key determinant in the signatures identified, in both periphery and tumor site, thus likely providing feasible biomarkers of ICB response.

Dataset Information

Prognostic significance of peripheral CD8+CD28+ and CD8+CD28- T cells in advanced non-small cell lung cancer patients treated with chemo(radio)therapy.

Publications

Prognostic significance of peripheral CD8+CD28+ and CD8+CD28- T cells in advanced non-small cell lung cancer patients treated with chemo(radio)therapy.

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