scholarly journals Interleukin-35 Suppresses the Antitumor Activity of T Cells in Patients with Non-Small Cell Lung Cancer

2018 ◽  
Vol 47 (6) ◽  
pp. 2407-2419 ◽  
Author(s):  
Hong-Min Wang ◽  
Xiao-Hong Zhang ◽  
Ming-Ming Feng ◽  
Yan-Jun Qiao ◽  
Li-Qun Ye ◽  
...  
Keyword(s):  
Lung Cancer ◽  
T Cells ◽  
Small Cell Lung Cancer ◽  
Cell Lung Cancer ◽  
Cd8 T Cells ◽  
Peripheral Blood ◽  
Cd4 T Cells ◽  
Small Cell ◽  
Small Cell Lung ◽  
Nsclc Patients

Background/Aims: Interleukin (IL)-35 has immunosuppressive functions in autoimmune diseases, infectious diseases, and certain cancers. However, few studies have focused on its immunoregulatory activity in non-small cell lung cancer (NSCLC). Thus, we investigated the role of IL-35 in the pathogenesis of this disease. Methods: A total of 66 NSCLC patients and 21 healthy individuals were enrolled. IL-35 expression in peripheral blood and bronchoalveolar lavage fluid (BALF) was measured. The modulatory functions of IL-35 on purified CD4+ and CD8+ T cells from NSCLC patients were investigated in direct and indirect coculture systems with NSCLC cell lines. Results: IL-35 expression was significantly increased in BALF from the tumor site, but not in the peripheral blood of NSCLC patients. IL-35 did not affect the bioactivity including proliferation, cytokine production, cell cycle, and cellular invasion of NSCLC cells. It suppressed responses from type 1 T helper (Th1) and Th17 cells but elevated the regulatory T cell response in cultured CD4+ T cells from NSCLC patients, and reduced cytokine-mediated CD4+ T cells cytotoxicity to NSCLC cells. Moreover, IL-35 also inhibited cytotoxic gene expression in CD8+ T cells from NSCLC, reducing their cytolytic and noncytolytic functions. Conclusion: The results of this study suggest that IL-35 contributes to the dysfunction/exhaustion of T cells and limited antitumor immune responses in NSCLC.

scholarly journals Expression of PD-1 on CD4+ T cells in peripheral blood associates with poor clinical outcome in non-small cell lung cancer

Oncotarget ◽  
2016 ◽  
Vol 7 (35) ◽  
pp. 56233-56240 ◽  
Author(s):  
Hong Zheng ◽  
Xin Liu ◽  
Jianhong Zhang ◽  
Shawn J. Rice ◽  
Matthias Wagman ◽  
...  
Keyword(s):  
Lung Cancer ◽  
T Cells ◽  
Clinical Outcome ◽  
Small Cell Lung Cancer ◽  
Cell Lung Cancer ◽  
Peripheral Blood ◽  
Cd4 T Cells ◽  
Small Cell ◽  
Small Cell Lung ◽  
Poor Clinical Outcome

scholarly journals Screening of T Cell-Related Long Noncoding RNA-MicroRNA-mRNA Regulatory Networks in Non-Small-Cell Lung Cancer

2020 ◽  
Vol 2020 ◽  
pp. 1-13
Author(s):  
Jinlong Duan ◽  
Yuefen Pan ◽  
Xi Yang ◽  
Liping Zhong ◽  
Yin Jin ◽  
...  
Keyword(s):  
Lung Cancer ◽  
T Cells ◽  
T Cell ◽  
Small Cell Lung Cancer ◽  
Cell Lung Cancer ◽  
Cd8 T Cells ◽  
Cd4 T Cells ◽  
Small Cell ◽  
Small Cell Lung ◽  
Memory Cd4 T Cells

Background. Lung cancer (LC) has the highest mortality rate among all the other types of cancer in the world. T cells are known to be the key factor in inducing the immune response during LC. Objective. In this study, we aimed to screen and analyze RNAs associated with CD8(+) T cells and activated memory CD4(+) T cells in lung adenocarcinomas, a subtype of non-small-cell lung cancer (NSCLC-LUAD). Methods. Gene expression RNA-seq data and clinical data of NSCLC-LUAD were downloaded from the XENA database. The data were divided into low scores and high scores based on the Stromal and Immune scores. Then, all the genes were screened for identifying those specifically associated with CD8(+) T cells and activated memory CD4(+) T cells. The screened genes were used for the construction of the protein-protein interaction (PPI) network and for Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis along with prognosis analysis. Based on the results of the prognostic analysis, the prognostic-related genes were used to analyze long noncoding (lnc)RNA-micro(mi)RNA-mRNA networks and to predict small chemical molecules. Results. According to the Immune and Stromal scores, a total of 885 upregulated and 29 downregulated RNAs were identified. A total of 90 differentially expressed genes (DEGs) were found to be related to CD8(+) T immune cells, and 48 DEGs were related to activated memory CD4(+) T cells. GPR174 and CD226 suggested a favorable prognosis. For CD8(+) and activated memory CD4(+) T cells, 112 and 113 PPI edges were obtained, respectively. GPR174 was found to be regulated by hsa-miR-19b-5p and hsa-miR-19b-2-5p, and both of these two miRNAs were regulated by lncRNA PCED1B-AS1. CD226 was regulated by hsa-miR-379-5p, which was in turn regulated by lncRNA RP11-81H14.2. Conclusion. Our findings provide a deeper understanding of the T cell-related ceRNA regulatory mechanism in NSCLC-LUAD pathogenesis.

scholarly journals Biomarkers and Gene Signatures to Predict Durable Response to Pembrolizumab in Non-Small Cell Lung Cancer

Cancers ◽  
2021 ◽  
Vol 13 (15) ◽  
pp. 3828
Author(s):  
Anello Marcello Poma ◽  
Rossella Bruno ◽  
Iacopo Pietrini ◽  
Greta Alì ◽  
Giulia Pasquini ◽  
...  
Keyword(s):  
Lung Cancer ◽  
T Cells ◽  
Small Cell Lung Cancer ◽  
Cell Lung Cancer ◽  
Immune Cell ◽  
Small Cell ◽  
Small Cell Lung ◽  
First Line ◽  
Durable Response ◽  
Nsclc Patients

Pembrolizumab has been approved as first-line treatment for advanced Non-small cell lung cancer (NSCLC) patients with tumors expressing PD-L1 and in the absence of other targetable alterations. However, not all patients that meet these criteria have a durable benefit. In this monocentric study, we aimed at refining the selection of patients based on the expression of immune genes. Forty-six consecutive advanced NSCLC patients treated with pembrolizumab in first-line setting were enrolled. The expression levels of 770 genes involved in the regulation of the immune system was analysed by the nanoString system. PD-L1 expression was evaluated by immunohistochemistry. Patients with durable clinical benefit had a greater infiltration of cytotoxic cells, exhausted CD8, B-cells, CD45, T-cells, CD8 T-cells and NK cells. Immune cell scores such as CD8 T-cell and NK cell were good predictors of durable response with an AUC of 0.82. Among the immune cell markers, XCL1/2 showed the better performance in predicting durable benefit to pembrolizumab, with an AUC of 0.85. Additionally, CD8A, CD8B and EOMES showed a high specificity (>0.86) in identifying patients with a good response to treatment. In the same series, PD-L1 expression levels had an AUC of 0.61. The characterization of tumor microenvironment, even with the use of single markers, can improve patients’ selection for pembrolizumab treatment.

546 The differentiation status of systemic PD1+ CD8 T cells is associated with favorable outcome to PD1 blockade therapy in non small cell lung cancer

2020 ◽  
Vol 8 (Suppl 3) ◽  
pp. A582-A582
Author(s):  
Asma Khanniche ◽  
Ying Wang
Keyword(s):  
Lung Cancer ◽  
T Cells ◽  
Small Cell Lung Cancer ◽  
Cell Lung Cancer ◽  
Cd8 T Cells ◽  
Small Cell ◽  
Favorable Outcome ◽  
Small Cell Lung ◽  
Differentiation Status ◽  
Pd1 Blockade

BackgroundNon small cell lung cancer is one of the cancer types where Immune checkpoint blockade has demonstrated unprecedented clinical efficiency. However, only a fraction of patients benefit from such therapy; factors determining this response are yet to be elucidated. Here, we investigated whether the differentiation status of circulating CD8 T cells might be associated with outcome of PD1 blockade therapy in NSCLC.MethodsWe used multi-parameter flow cytometry to study CD8 T cell differentiation states in NSCLC patients at baseline and to examine the effects of blocking the PD1/PDL1 pathway on those cells.ResultsWe found that responders to PD1 blockade therapy has more peripheral PD1+ CD8 T cells with an early-like differentiated status at baseline and that this phenotype is associated with longer survival. Moreover, PD1 blockade induced reinvigoration is mostly observed in cells with this with an early-like differentiated status.ConclusionsAn early like differentiation status of peripheral CD8 T cells is associated with favorable outcome of PD1 blockade immunotherapy

scholarly journals Durvalumab and tremelimumab with or without stereotactic body radiation therapy in relapsed small cell lung cancer: a randomized phase II study

2020 ◽  
Vol 8 (2) ◽  
pp. e001302
Author(s):  
Suchita Pakkala ◽  
Kristin Higgins ◽  
Zhengjia Chen ◽  
Gabriel Sica ◽  
Conor Steuer ◽  
...  
Keyword(s):  
Lung Cancer ◽  
T Cells ◽  
Radiation Therapy ◽  
Small Cell Lung Cancer ◽  
Cell Lung Cancer ◽  
Peripheral Blood ◽  
Stereotactic Body Radiation Therapy ◽  
Small Cell ◽  
Small Cell Lung ◽  
Stereotactic Body Radiation

BackgroundImmune checkpoint blockade (ICB) targeting programmed cell death protein 1 and cytotoxic T lymphocyte-associated protein 4 has achieved modest clinical activity as salvage therapy in relapsed small cell lung cancer (SCLC). We conducted this signal-finding study to assess the efficacy of ICB with or without radiation in relapsed SCLC.MethodsPatients with relapsed SCLC and ≤2 previous lines of therapy were randomized to (1) arm A: durvalumab (D) 1500 mg/tremelimumab (T) 75 mg (intravenously every 4 weeks without stereotactic body radiation therapy (SBRT)) or (2) arm B: immune-sensitizing SBRT to one selected tumor site (9 Gy × 3 fractions) followed by D/T. Treatment continued until progression or a maximum of 12 months. The co-primary endpoints of the study were overall response rate (ORR) and progression-free survival (PFS). We evaluated circulating lymphocyte repertoire in serial peripheral blood samples and tumor infiltrating lymphocytes (TILs) from on-treatment biopsies as pharmacodynamic markers.ResultsEighteen patients were randomized to arms A and B (n=9 each): median age 70 years; 41.2% women. The median PFS and ORR were 2.1 months and 0% in arm A and 3.3 months and 28.6% in arm B. The median overall survival (OS) was 2.8 months in arm A and 5.7 months in arm B (p=0.3772). Pooled efficacy of D/T±SBRT in 15 Response evaluation criteria in solid tumors (RECIST) evaluable patients across both arms showed the best ORR in terms of partial response in 13.3%, stable disease in 26.6% and progressive disease in 60.0%; the overall median PFS and OS were 2.76 and 3.9 months. The most common adverse events were grade 1 fatigue (66%) and grade 1 elevated amylase (56%) in arm A, and grade 1 fatigue (56%) and pain (44%) in arm B. There was a significant increase in activated CD8(+)ICOS+ T cells (p=0.048) and a reduction in naïve T cells (p=0.0454) in peripheral blood following treatment, along with a significant amount of activated CD8+ICOS+ T cells in TILs from responders.ConclusionsThe D/T combination with and without SBRT was safe but did not show sufficient efficacy signal in relapsed SCLC. Changes in peripheral blood lymphocyte and TILs were consistent with an immunologic response.Trial registration numberNCT02701400.

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

2019 ◽  
Vol 17 (1) ◽  
Author(s):  
Chao Liu ◽  
Wang Jing ◽  
Ning An ◽  
Aijie Li ◽  
Weiwei Yan ◽  
...  
Keyword(s):  
Lung Cancer ◽  
T Cells ◽  
Small Cell Lung Cancer ◽  
Natural Killer ◽  
Cell Lung Cancer ◽  
Advanced Nsclc ◽  
Small Cell ◽  
Small Cell Lung ◽  
Radio Therapy ◽  
Nsclc Patients

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, γδT 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 < 0.05) than SCCs. Conclusions Our findings uncovered the prognostic values of peripheral CD8+CD28+ T cells and CD8+CD28− T cells in advanced NSCLC patients treated with chemo(radio)therapy, which could help to identify patients with poor outcomes and refine treatment strategies.

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