Single-Cell Profiling of Kidney Transplant Recipients With Immunosuppressive Treatment Reveals the Dynamic Immune Characteristics

Kidney transplantation is currently the first choice of treatment for various types of end-stage renal failure, but there are major limitations in the application of immunosuppressive protocols after kidney transplantation. When the dose of immunosuppressant is too low, graft rejection occurs easily, while a dose that is too high can lead to graft loss. Therefore, it is very important to explore the immune status of patients receiving immunosuppressive agents after kidney transplantation. To compare the immune status of the recipient’s whole peripheral blood before and after receipt of immunosuppressive agents, we used single-cell cytometry by time-of-flight (CyTOF) to detect the peripheral blood immune cells in five kidney transplant recipients (KTRs) from the Department of Organ Transplantation of Zhujiang Hospital of Southern Medical University before and after receiving immunosuppressive agents. Based on CyTOF analysis, we detected 363,342 live single immune cells. We found that the immune cell types of the KTRs before and after receipt of immunosuppressive agents were mainly divided into CD4+ T cells, CD8+ T cells, B cells, NK cells/γδ T cells, monocytes/macrophages, granulocytes, and dendritic cells (DCs). After further reclustering of the above cell types, it was found that the immune cell subclusters in the peripheral blood of patients underwent major changes after receipt of immunosuppressants. After receiving immunosuppressive therapy, the peripheral blood of KTRs had significantly increased levels of CD57+NK cells and significantly decreased levels of central memory CD4+ T cells, follicular helper CD4+ T cells, effector CD8+ T cells, effector memory CD8+ T cells and naive CD8+ T cells. This study used CyTOF to classify immune cells in the peripheral blood of KTRs before and after immunosuppressive treatment, further compared differences in the proportions of the main immune cell types and immune cell subgroups before and after receipt of immunosuppressants, and provided relatively accurate information for assessment and treatment strategies for KTRs.

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Immunosuppressive milieu of high-risk localized prostate cancer.

Journal of Clinical Oncology ◽

10.1200/jco.2020.38.6_suppl.344 ◽

2020 ◽

Vol 38 (6_suppl) ◽

pp. 344-344

Author(s):

Victor Ricardo Adorno Febles ◽

Dennis Adeegbe ◽

Aarif Ahsan ◽

Jiansheng Wu ◽

Alireza Khodadad-Jamayran ◽

...

Keyword(s):

Prostate Cancer ◽

T Cells ◽

Regulatory T Cells ◽

Cd8 T Cells ◽

Peripheral Blood ◽

Immune Cell ◽

Histological Grade ◽

Statistical Significance ◽

Cell Types ◽

Localized Prostate Cancer

344 Background: The immune factors that modulate the aggressiveness of localized treatment-naïve prostate cancer remain poorly understood. Methods: Fresh tumor and peripheral blood were collected at the time of radical prostatectomy in patients with localized prostate cancer. We evaluated the immune cell composition of 22 patient samples employing multi-parametric flow cytometry. Samples were grouped by histological grade into intermediate (INTPCA) and high-grade (HIGHPCA) prostate cancers based on standard NCCN criteria and immune cell abundances were quantified by mean +/- SEM. Statistical significance was assessed using the Mann-Whitney test. Results: INTPCA and HIGHPCA tumors harbored a similar increase in CD8+ T cells ( p < 0.0005 and p < 0.05, respectively) and CD11b+CD68-CD16+ myeloid-derived cells (p < 0.05) relative to the peripheral blood. Other cell types were similarly decreased in both INTPCA and HIGHPCA, including CD11b+CD68+CD14+ ( p < 0.005 and p < 0.05, respectively). By contrast, regulatory T cells were the only cell type in our analysis to be uniquely enriched in HIGHPCA rather than INTPCA ( p < 0.05). The most unique feature found in phenotypic profiling of the immune repertoire of HIGHPCA relative to INTPCA was an increase in the immune inhibitory receptor ligand, PD-L1, in the tumor associated macrophages (CD11b+CD68+CD14+) compared to the periphery (p < 0.05). Conclusions: Collectively, our findings reveal that HIGHPCA harbors a distinct immunological landscape. Although effector CD8+ T cells are preferentially expressed in the tumor, these are met with an increased proportion of regulatory T cells as well as PD-L1 expressing macrophages that contribute to the inert tumor microenvironment. These are key features of aggressive prostate cancer that may serve as potential biomarkers and therapeutic targets.

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The Numerical Predominance and Large Transcriptome Differences of Neutrophils in Peripheral Blood Together Inevitably Account for a Reported Pulmonary Tuberculosis Signature

International Journal of Genomics ◽

10.1155/2017/5830971 ◽

2017 ◽

Vol 2017 ◽

pp. 1-8 ◽

Cited By ~ 2

Author(s):

Kang Wu ◽

Ka-Wing Wong ◽

Wang-Long Deng ◽

Hao Zhang ◽

Jing Li ◽

...

Keyword(s):

T Cells ◽

Pulmonary Tuberculosis ◽

Cd8 T Cells ◽

Whole Blood ◽

Peripheral Blood ◽

Cd4 T Cells ◽

Cell Types ◽

Transcriptional Responses ◽

Inducible Genes ◽

Transcript Signature

Previous transcriptomic analysis revealed a 393-transcript signature (PTBsig), which is dominated by interferon inducible genes, in whole blood of pulmonary tuberculosis (PTB) patients. Comparisons with a limited set of interferon-driven genes among separated monocytes, CD4+ T cells, CD8+ T cells, and neutrophils indicated that the signature is due to changes in neutrophils, the overwhelmingly predominant cell type. By extending the analysis to the entire 393 transcripts of PTBsig and by switching the cell proportions between separated monocytes, CD4+ T cells, CD8+ T cells, and neutrophils, we create putative PTBsig for whole blood (pPTBsig) in which CD4+ or CD8+ T cells or monocytes predominated or in which the cell proportions were unchanged. These putative signatures are then compared to the actual reported PTBsig. We show that, because of their predominance in peripheral blood and their larger transcriptional responses, neutrophils were indeed almost exclusively responsible for PTBsig. We caution that the functional significance of changes in other cell types might escape notice in transcriptome analysis that is based upon whole blood.

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Environmental Air Pollutants Inhaled during Pregnancy Are Associated with Altered Cord Blood Immune Cell Profiles

International Journal of Environmental Research and Public Health ◽

10.3390/ijerph18147431 ◽

2021 ◽

Vol 18 (14) ◽

pp. 7431

Author(s):

Gabriela Martins Costa Gomes ◽

Wilfried Karmaus ◽

Vanessa E. Murphy ◽

Peter G. Gibson ◽

Elizabeth Percival ◽

...

Keyword(s):

T Cells ◽

Cord Blood ◽

Cd8 T Cells ◽

Cd4 T Cells ◽

Air Pollutants ◽

Immune Cell ◽

Principal Component ◽

Ambient Air ◽

Cell Types ◽

Air Pollutant

Air pollution exposure during pregnancy may be a risk factor for altered immune maturation in the offspring. We investigated the association between ambient air pollutants during pregnancy and cell populations in cord blood from babies born to mothers with asthma enrolled in the Breathing for Life Trial. For each patient (n = 91), daily mean ambient air pollutant levels were extracted during their entire pregnancy for sulfur dioxide (SO2), nitric oxide, nitrogen dioxide, carbon monoxide, ozone, particulate matter <10 μm (PM10) or <2.5 μm (PM2.5), humidity, and temperature. Ninety-one cord blood samples were collected, stained, and assessed using fluorescence-activated cell sorting (FACS). Principal Component (PC) analyses of both air pollutants and cell types with linear regression were employed to define associations. Considering risk factors and correlations between PCs, only one PC from air pollutants and two from cell types were statistically significant. PCs from air pollutants were characterized by higher PM2.5 and lower SO2 levels. PCs from cell types were characterized by high numbers of CD8 T cells, low numbers of CD4 T cells, and by high numbers of plasmacytoid dendritic cells (pDC) and low numbers of myeloid DCs (mDCs). PM2.5 levels during pregnancy were significantly associated with high numbers of pDCs (p = 0.006), and SO2 with high numbers of CD8 T cells (p = 0.002) and low numbers of CD4 T cells (p = 0.011) and mDCs (p = 4.43 × 10−6) in cord blood. These data suggest that ambient SO2 and PM2.5 exposure are associated with shifts in cord blood cell types that are known to play significant roles in inflammatory respiratory disease in childhood.

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SAT0352 AN UNSUPERVISED ANALYSIS IDENTIFIES A SPECIFIC IMPACT OF BIOLOGICS ON T LYMPHOCYTE PHENOTYPES.

Annals of the Rheumatic Diseases ◽

10.1136/annrheumdis-2020-eular.3838 ◽

2020 ◽

Vol 79 (Suppl 1) ◽

pp. 1122.1-1122

Author(s):

N. Rosine ◽

G. Millot ◽

S. Koturan ◽

C. Leloup ◽

H. Yahia ◽

...

Keyword(s):

T Cells ◽

Cd8 T Cells ◽

Cd4 T Cells ◽

Immune Cell ◽

Specific Subset ◽

Number Of Patients ◽

Before And After ◽

System Data ◽

The One ◽

The Impact

Background:It is currently not known if TNF or IL-17A inhibitors have an impact on immune cell frequencies in axial Spondyloarthritis (AxSpA). This question is important to understand the impact of biologics on the immune system. Data from clinical trials didn’t show significant modification on immune cells and especially on lymphocytes. But regarding the risk of infections linked to these treatments lymphocyte cell subsets are certainly disturbed. Moreover, biologics could affect subsets of cells with an unusual phenotype.Objectives:To identify the phenotype of cell subsets affected by biologics.Methods:We used an “unsupervised approach” to analyze CD4+ T cells and CD8+T cells subsets. Contrary to a “supervised approach”, this strategy takes advantages of the fluorescence emitted by all of the surface markers used to characterize the cells at the same time. The objective was on the one hand to overcome statistical problems related to the number of patients and the repetition of the tests and on the other hand to increase the sensitivity of the analysis by identifying and analyzing new cell populations. The first step was to cluster the cells based on a selection of 12 T cells markers characteristic of the classical cell subsets and the stage of maturation to obtain cell clusters with a phenotype based on the combination of these 12 markers. Then, we were able to describe “a posteriori” the change of frequency of the clusters identified. The second step was to create a visualization of the cells affected to confirm their existence in a classical flow cytometry gate. With this pipeline, we analyzed CD4 and CD8 T cells isolated from a group of AxSpA patients (n=7) before and after 3 months of TNF therapy and a group of patients (n=6) before and after 4 months of IL-17A therapy.Results:We observed that after biologics CD4 and CD8 T cells frequencies did not change but there was a redistribution of the different clusters analyzed. Specifically, we identified for CD4+T cells after anti TNF treatment an increase of 2 clusters (CD4+CD27+CD45RA+Va7.2intCD161int and CD4+CD27-CD45RA-CCR6+CD161int) and a decrease of 3 clusters (CD4+CD27+CD45RA+CRTH2intCD161int, CD4+ CD27+CD45RA+CXCR3+, CD4+CD27+CD45RA+gdint CD161int) and for CD8+T cells a decrease of 1 cluster after treatment (CD8+ CD27+CD45RA+CD161+CXCR3+) and an increase of 1 cluster (CD8+ CD27+CD45RA+). The clusters affected by anti-IL-17A therapy were different. For CD4+T cells, we identified a decrease of 2 clusters (CD4+CD27+CD45RA+CXCR5+ CD161+ and CD4+CD27+CD45RA- CXCR3+CCR6+CD161+) and an increase of 2 clusters (CD4+CD27+CD45RA+gdintCD161+, CD4+CD27+ CRTH2intCCR6+) and for CD8+T cells a decrease of 1 cluster (CD8+CD27+CD45RA+ CXCR3+CRTH2intCD161int) and an increase of 1 cluster (CD8+CD27+CD45RA+CXCR3intCD161-).Conclusion:We identified 5 different clusters in CD4+T cells affected by anti TNF and 4 by anti-IL-17A. We identified 2 clusters in CD8+T cells affected by anti TNF and 2 by anti-IL-17A. The phenotypes of these clusters were unexpected and raised new questions about the effect of biologics in AxSpA. We were also able to create a visualization of these cells affected by biologics in a “classic gating view” which will help us to perform scRNAseq. With this unique approach, we show an impact of biologics on the frequency of very specific subset of CD4+ and CD8+ T cells in AxSpAFigure 1.Disclosure of Interests:None declared

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Whole Blood Transcriptome Analysis Reveals the Correlation between Specific Immune Cells and Septicemic Melioidosis

Disease Markers ◽

10.1155/2021/6166492 ◽

2021 ◽

Vol 2021 ◽

pp. 1-13

Author(s):

Ke Xu ◽

Dahua Xu ◽

Hua Pei ◽

Yunfan Quan ◽

Jun Liu ◽

...

Keyword(s):

Immune Response ◽

T Cells ◽

Cd8 T Cells ◽

Immune Cells ◽

Immune Cell ◽

Expression Patterns ◽

Multivariate Logistic Regression Analysis ◽

Cell Types ◽

Host Immune System ◽

Resting Cells

Melioidosis is a serious infectious disease caused by the environmental Gram-negative bacillus Burkholderia pseudomallei. It has been shown that the host immune system, mainly comprising various types of immune cells, fights against the disease. The present study was to specify correlation between septicemic melioidosis and the levels of multiple immune cells. First, the genes with differential expression patterns between patients with septicemic melioidosis (B. pseudomallei) and health donors (control/healthy) were identified. These genes being related to cytokine binding, cell adhesion molecule binding, and MHC relevant proteins may influence immune response. The Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis revealed 23 enriched immune response pathways. We further leveraged the microarray data to investigate the relationship between immune response and septicemic melioidosis, using the CIBERSORT analysis. Comparison of the percentages of 22 immune cell types in B. pseudomallei vs. control/healthy revealed that those of CD4 memory resting cells, CD8+ T cells, B memory cells, and CD4 memory activated cells were low, whereas those of M0 macrophages, neutrophils, and gamma delta T cells were high. The multivariate logistic regression analysis further revealed that CD8+ T cells, M0 macrophages, neutrophils, and naive CD4+ cells were strongly associated with the onset of septicemic melioidosis, and M2 macrophages and neutrophils were associated with the survival in septicemic melioidosis. Taken together, these data point to a complex role of immune cells on the development and progression of melioidosis.

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Differential Immune Landscape of Hepatocellular Carcinoma Suggests Potential role of Macrophages in Hepatocarcinogenesis

Pakistan Journal of Medical Sciences ◽

10.12669/pjms.37.3.2973 ◽

2021 ◽

Vol 37 (3) ◽

Author(s):

Yusra Shafique ◽

Muhammad Asif Qureshi ◽

Saeed Khan ◽

Talat Mirza

Keyword(s):

Hepatocellular Carcinoma ◽

T Cells ◽

B Cells ◽

Cd8 T Cells ◽

Immune Cells ◽

Cd4 T Cells ◽

Potential Role ◽

Immune Cell ◽

P Value

Objectives: To investigate immune cell densities in tumor microenvironment of hepatocellular carcinoma. Methods: This cross-sectional study was conducted during 2017-2019 at the Dow University of Health Sciences Karachi. A total of 42 subsequent patients undergoing liver biopsy/resection and diagnosed with hepatocellular carcinoma were included in the study. Moreover, a total of 10 control tissues were also included. In order to investigate immune cells densities in hepatocellular carcinoma, immunohistochemistry was performed using antibodies including α-MPO(neutrophils), α-CD-68(macrophages), α-CD-3(T-cells), α-CD-20(B-cells), α-CD-4(CD4+ T-cells) and α-CD-8(CD8+ T-cells). Quantification of immune cells/mm2 was performed as per the College of American Pathologists’ guidelines. Data were analyzed using SPSS version 21. A p-value of 0.05 was considered significant at all times. Results: We report significantly increased infiltration of macrophages (mean macrophages= 306.57/mm2, p-value<0.05), moderately significant infiltration of neutrophils (p-value=0.06) and B-cells (p-value=0.07) while no significant infiltration of CD4+T-cells (p- value=0.31), and CD8+T-cells (p-value=0.39) in tumour microenvironment of patients with hepatocellular carcinoma. Conclusion: We provide evidence for increased macrophage infiltration in liver cancer microenvironment suggesting a potential role of these cells in hepatocarcinogenesis. doi: https://doi.org/10.12669/pjms.37.3.2973 How to cite this:Shafique Y, Qureshi MA, Khan S, Mirza T. Differential Immune Landscape of Hepatocellular Carcinoma Suggests Potential role of Macrophages in Hepatocarcinogenesis. Pak J Med Sci. 2021;37(3):---------. doi: https://doi.org/10.12669/pjms.37.3.2973 This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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The immune cell landscape of peripheral blood mononuclear cells from PNS patients

Scientific Reports ◽

10.1038/s41598-021-92573-6 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Qing Ye ◽

Chao Zhou ◽

Sisi Li ◽

Jingjing Wang ◽

Fei Liu ◽

...

Keyword(s):

T Cells ◽

Nephrotic Syndrome ◽

B Cells ◽

Nk Cells ◽

Cd8 T Cells ◽

Immune Cells ◽

Peripheral Blood ◽

Mononuclear Cells ◽

Immune Cell ◽

Immunological Mechanism

AbstractExisting research suggests that the human immune system and immune cells are involved in the pathogenesis of nephrotic syndrome, but there is still a lack of direct evidence. This study tried to analyze the profiling of immune cells in the peripheral blood of steroid-sensitive nephrotic syndrome (SSNS) patients and steroid-resistant nephrotic syndrome (SRNS) patients before and after standard steroid treatment to clarify the immunological mechanism of nephrotic syndrome patients. The number and proportion of CD4 + T cells in patients with nephrotic syndrome remained unchanged. However, there is an imbalance of Th1 and Th2 and an excessive increase of Th17 cells. The number of CD8 + T cells and the number of effector CD8 + T cells in them increased significantly, but only in SSNS, the number of activated CD8 + T cells increased, and the number of activated Treg cells decreased significantly. Nephrotic syndrome patients also have B cell disorder, and it is more prominent in SSNS patients. Compared with the normal control, only the number of B cells and plasmablast in SSNS patients increased significantly (Z = − 2.20, P = 0.028). This study also observed that transitional B cells decreased in both SSNS and SRNS patients, but SSNS patients' decrease was lower than in SRNS patients. Compared with normal controls, monocytes in patients with nephrotic syndrome decreased significantly. The main reason was that Non-classical Monocyte decreased, while Classical Monocyte increased slightly. The total number of NK cells did not change, but the internal cell subgroups' composition occurred. Changes, realized as CD56hi NK cells increased, CD56low NK cells decreased; and the above trend is more evident in SSNS patients. Patients with nephrotic syndrome have immune disorders, including T cells, B cells, Monocytes, and NK cells. It can be confirmed that immune factors are involved in the pathogenesis of the nephrotic syndrome.

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Role of IL-4-Producing CD8+ T Cells in Patients with Chronic Graft-Versus-Host Disease (cGVHD) and in Normal Healthy Volunteer.

Blood ◽

10.1182/blood.v104.11.4970.4970 ◽

2004 ◽

Vol 104 (11) ◽

pp. 4970-4970

Author(s):

Kengo Nakamura ◽

Masashi Takebayashi ◽

Kenichirou Tajima ◽

Tsutomu Tanijiri ◽

Takashi Yokoi ◽

...

Keyword(s):

T Cells ◽

Healthy Volunteers ◽

Cd8 T Cells ◽

Peripheral Blood ◽

Cd4 T Cells ◽

Cytokine Production ◽

Chronic Gvhd ◽

Immunosuppressive Agents ◽

Surface Marker

Abstract The pathophysiology of cGVHD still remains unclear. To gain more insight into the immunological mechanism of cGVHD, we examined surface marker and cytokine production of peripheral blood T cells from 19 patients in the chronic phase of allogeneic hematopoietic stem cell transplantation (allo-HSCT). The median age of patients was 31 years (range 13–47 years). The median days from allo-HSCT to examination was 43 months (range 17–94 months). Ten patients in whom 6 have treated with immunosuppressive agents and 4 without them developed chronic GVHD, whereas 9 patients in whom 5 have treated with immunosuppressive agents and 4 without them did not develop chronic GVHD. Peripheral blood mononuclear cells were extracted from patients and 10 healthy volunteers, followed by isolation into CD4+ T cells and CD8+ T cells. The analysis of surface marker and intracellular cytokine production of these cells was performed using fluorescence activated cell sorter. The percentage of IFN-g-producing CD8+ T cells among CD8+ T cells was significantly higher in patients with or without cGVHD than in healthy volunteers (p<0.001). Since all 19 patients were in remission, the IFN-g-producing CD8+ T cells might be related to graft-versus-leukemia effect. On the other hand, the percentage of IL-4-producing CD8+ T cells among CD8+ T cells was significantly higher in patients with cGVHD (mean 3.3%, range 1.3–8.2%) than in patients without cGVHD (mean 1.2%, range 0.8–1.7%) and healthy volunteers (mean 1.1%, range 0.1–1.6%) (both p<0.001). By contrast, the percentage of IL-4-producing CD4+ T cells was not different among patients with and without cGVHD and healthy volunteers. Then, we minutely explored the immunological role of IL-4-producing CD8+ T cells in healthy volunteers. These cells expressed the surface marker of CD25, CCR4 and CTLA-4. In the analysis of cytokine production in these cells, we identified the type 2 cytokine, such as IL-4, IL-5, IL-10, and IL-13, although we could not find IFN-g. In conclusion, these findings suggest that IL-4-producing CD8+ T cells may be an immunological marker of cGVHD in which these cells may play a crucial role as regulatory T cells.

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Immune classification of clear cell renal cell carcinoma

Scientific Reports ◽

10.1038/s41598-021-83767-z ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Sumeyye Su ◽

Shaya Akbarinejad ◽

Leili Shahriyari

Keyword(s):

T Cells ◽

Cd8 T Cells ◽

Renal Cell ◽

Cd4 T Cells ◽

Immune Cell ◽

Clear Cell ◽

P Value ◽

Cell Type ◽

Primary Tumors ◽

Immune Cell Type

AbstractSince the outcome of treatments, particularly immunotherapeutic interventions, depends on the tumor immune micro-environment (TIM), several experimental and computational tools such as flow cytometry, immunohistochemistry, and digital cytometry have been developed and utilized to classify TIM variations. In this project, we identify immune pattern of clear cell renal cell carcinomas (ccRCC) by estimating the percentage of each immune cell type in 526 renal tumors using the new powerful technique of digital cytometry. The results, which are in agreement with the results of a large-scale mass cytometry analysis, show that the most frequent immune cell types in ccRCC tumors are CD8+ T-cells, macrophages, and CD4+ T-cells. Saliently, unsupervised clustering of ccRCC primary tumors based on their relative number of immune cells indicates the existence of four distinct groups of ccRCC tumors. Tumors in the first group consist of approximately the same numbers of macrophages and CD8+ T-cells and and a slightly smaller number of CD4+ T cells than CD8+ T cells, while tumors in the second group have a significantly high number of macrophages compared to any other immune cell type (P-value $$<0.01$$ < 0.01 ). The third group of ccRCC tumors have a significantly higher number of CD8+ T-cells than any other immune cell type (P-value $$<0.01$$ < 0.01 ), while tumors in the group 4 have approximately the same numbers of macrophages and CD4+ T-cells and a significantly smaller number of CD8+ T-cells than CD4+ T-cells (P-value $$<0.01$$ < 0.01 ). Moreover, there is a high positive correlation between the expression levels of IFNG and PDCD1 and the percentage of CD8+ T-cells, and higher stage and grade of tumors have a substantially higher percentage of CD8+ T-cells. Furthermore, the primary tumors of patients, who are tumor free at the last time of follow up, have a significantly higher percentage of mast cells (P-value $$<0.01$$ < 0.01 ) compared to the patients with tumors for all groups of tumors except group 3.

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

Cellular Physiology and Biochemistry ◽

10.1159/000491615 ◽

2018 ◽

Vol 47 (6) ◽

pp. 2407-2419 ◽

Cited By ~ 13

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.

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