Interleukin-10-regulated tumour tolerance in non-small cell lung cancer

Vahl, Julius Malte; Friedrich, Juliane; Mittler, Susanne; Trump, Sonja; Heim, Lisanne; Kachler, Katerina; Balabko, Liubov; Fuhrich, Nicole; Geppert, Carol-Immanuel; Trufa, Denis I.; Sopel, Nina; Rieker, Ralf J.; Sı̂rbu, Horia; Finotto, Susetta

doi:10.1038/bjc.2017.336

Cited by 80 publications

(67 citation statements)

References 47 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Previous studies from our group and Supplementary Table S1 summarise some clinical data of the patients. 7,[17][18][19] The diagnosis of lung cancer was based on pathological confirmation, and histologic types of lung cancer were classified according to the World Health Organisation histologic classification formulated in 2004. The staging of lung cancer was based on the Cancer TNM Staging Manual formulated by the International Association for the Study of Lung Cancer in 2010.…”

Section: Methodsmentioning

confidence: 99%

“…The clinico-pathological characteristics of the patients are shown in Supplementary Table S1 and were recently reported. 7,[17][18][19][20] We first performed IHC on histological tissue arrays, which were generated by using lung tissues dissected from the tumoral (TU) region as well as the tumour-free control (CTR) region of the lung of patients with NSCLC ( Fig. S1A).…”

Section: Increased Immunosuppressive Il-35 + Cells In the Lung Tu Regmentioning

confidence: 99%

“…Furthermore, thyroid transcription factor 1 (TTF-1) is routinely tested in the diagnostic evaluation of suspected lung cancers. However, considering the recent success of anti-PD-L1 antibody immunotherapy for lung cancer, 17 the significance of TTF-1 + PD-L1 + cells needs further investigation. 24 We thus asked whether TTF-1 + programmed cell death ligand 1(PD-L1) + cells in NSCLC would correlate with the presence of the immunosuppressive IL-35 + cells.…”

Section: Increased Immunosuppressive Il-35 + Cells In the Lung Tu Regmentioning

confidence: 99%

See 2 more Smart Citations

Increased expression of the immunosuppressive interleukin-35 in patients with non-small cell lung cancer

et al. 2019

Self Cite

View full text Add to dashboard Cite

BACKGROUND: The immunosuppressive role of the cytokine IL-35 in patients with non-small cell lung cancer (NSCLC) is poorly understood. In this study, we analysed the localisation and regulation of IL-35 in the lung of patients with non-small cell lung cancer (NSCLC) to further elucidate the immune-escape of cancer cells in perioperative course of disease. METHODS: Interleukin 35 (IL-35) was measured by ELISA in postoperative serum from 7 patients with NSCLC as well as 8 samples from healthy controls. Immunohistochemistry, FACS analysis, real-time PCR, as well as western blot from samples of the control (CTR), peri-tumoural (PT) and the tumoural (TU) region of the lung derived from patients with NSCLC and 10 controls were performed. RESULTS: Here we found elevated levels of IL-35 in the TU region as well as postoperative serum from patients with lung adenocarcinoma. Consistently, we found an increased expression of IL-35 + Foxp-3 + cells, which associated with ARG1 mRNA expression and decreased TNFA in the TU region of the lung of patients with NSCLC as compared to their CTR region. Furthermore, in the CTR region of the lung of patients with NSCLC, CD68 + macrophages were induced and correlated with IL-35 + cells. Finally, IL-35 positively correlated with TTF-1 + PD-L1 + cells in the TU region of NSCLC patients. CONCLUSIONS: Induced IL-35 + Foxp3 + cell numbers in the TU region of the lung of patients with NSCLC associated with ARG1 mRNA expression and with TTF-1 + PD-L1 + cells. In the tumour-free CTR area, IL-35 correlated with CD68 + macrophages. Thus inhibitors to IL-35 would probably succeed in combination with antibodies against immune checkpoints like PD-L1 and PD-1 currently used against NSCLC because they would inhibit immunosuppressive macrophages and T regulatory cells while promoting T cell-mediated anti-tumoural immune responses in the microenvironment as well as the TU region of NSCLC patients.

show abstract

Section: Methodsmentioning

confidence: 99%

Section: Increased Immunosuppressive Il-35 + Cells In the Lung Tu Regmentioning

confidence: 99%

Section: Increased Immunosuppressive Il-35 + Cells In the Lung Tu Regmentioning

confidence: 99%

See 1 more Smart Citation

Increased expression of the immunosuppressive interleukin-35 in patients with non-small cell lung cancer

et al. 2019

Self Cite

View full text Add to dashboard Cite

show abstract

“…Using neutralizing antibodies, we found that PD-1 þ Tim3 þ CD8 þ TILs from both mouse and human tumor tissues exert their suppressive function via the production of IL10 and require cell contact. The cytokine IL10 regulates cytotoxic T-cell responses in cancer (51,52). IL10-producing CD8 þ T cells are negative regulators of T-cell responses, particularly in autoimmune, viral infection models, and in tumor microenvironments (33,53,54).…”

Section: Cd8 þ Tils Express Ligands For Pd-1 and Tim-3mentioning

confidence: 99%

Immune-Checkpoint Blockade Opposes CD8+ T-cell Suppression in Human and Murine Cancer

Pfannenstiel

Díaz-Montero

Tian

et al. 2019

Cancer Immunology Research

View full text Add to dashboard Cite

Immune-checkpoint blockade enhances antitumor responses against cancers. One cancer type that is sensitive to checkpoint blockade is squamous cell carcinoma of the head and neck (SCCHN), which we use here to study limitations of this treatment modality. We observed that CD8 þ tumor-infiltrating lymphocytes (TILs) in SCCHN and melanoma express excess immune checkpoints components PD-1 and Tim-3 and are also CD27 À /CD28 À , a phenotype we previously associated with immune dysfunction and suppression. In ex vivo experiments, patients' CD8 þ TILs with this phenotype suppressed proliferation of autologous peripheral blood T cells. Similar phenotype and function of TILs was observed in the TC-1 mouse tumor model. Treatment of TC-1 tumors with anti-PD-1 or anti-Tim-3 slowed tumor growth in vivo and reversed the suppressive function of multi-checkpoint þ CD8 þ TIL. Similarly, treatment of both human and mouse PD-1 þ Tim-3 þ CD8 þ TILs with anticheckpoint antibodies ex vivo reversed their suppressive function. These suppressive CD8 þ TILs from mice and humans expressed ligands for PD-1 and Tim-3 and exerted their suppressive function via IL10 and close contact. To model therapeutic strategies, we combined anti-PD-1 blockade with IL7 cytokine therapy or with transfer of antigen-specific T cells. Both strategies resulted in synergistic antitumor effects and reduced suppressor cell function. These findings enhance our understanding of checkpoint blockade in cancer treatment and identify strategies to promote synergistic activities in the context of other immunotherapies.

show abstract

“…IL-12 can induce the production of IFN-γ, stimulate the proliferation and activation of CD8 + T lymphocytes, and play a role in promoting the anti-tumor immune response [28,29]. As an immunosuppressive factor, IL-10 can not only inhibit the apoptosis of tumor cells but also inhibit the role of IFN-γ and the anti-tumor immune response [28,30]. In our study, on days 7 and 14 after radiation, IL-12 and INF-γ levels in the SBHFRT group were obviously higher than those in the CFRT group, and IL-10 level was obviously lower than that in the CFRT group.…”

Section: Discussionmentioning

confidence: 99%

Relationship Between the Invasion of Lymphocytes and Cytokines in the Tumor Microenvironment and the Interval After Single Brachytherapy Hypofractionated Rradiotherapy and Conventional Fractionation Radiotherapy in Non-Small Cell Lung Cancer

Lin

Yue

Han

et al. 2020

Preprint

View full text Add to dashboard Cite

Background Lymphocytes and cytokines in tumor microenvironment are the key to immunotherapy, The effect of brachytherapy on tumor microenvironment is not clear. The aim of our study was to analyze the relationship between the invasion of lymphocytes and cytokines in the tumor microenvironment and the interval after single brachytherapy hypofractionated radiotherapy (SBHFRT) and conventional fractionation radiotherapy (CFRT) in non-small cell lung cancer (NSCLC). Methods Lewis tumor-bearing mice were randomly divided into control, CFRT and SBHFRT groups. On the days 7 and 14 after radiation, the expression rates of CD4+, CD8+, Foxp3+, and CD86 + cells and levels of Ki-67 + protein were detected by immunohistochemical analysis, and the tumor necrosis rate was calculated. Following this, interleukin-10 (IL-10), IL-12, and interferon-γ (INF-γ) levels were detected by enzyme-linked immunosorbent assay. The apoptosis rate was evaluated via flow cytometry. The tumor volume and tumor growth inhibition rate (TGIR) were calculated on day 14. Tumor metabolism was assessed via micro 18F-FDG positron emission tomography/computer tomography. Results The tumor volume in the SBHFRT group reduced by 22.0% and TGIR increased by 92.2% (P < 0.05). Further, on days 7 and 14 after radiation, tumor metabolism, Ki-67 + and Foxp3 + expression rates, and IL-10 levels were lower and tumor necrosis and apoptosis rates; CD86+, CD4+, and CD8 + expression rates; and IL-12 and INF-γ levels were higher in SBHFRT group than in the CFRT group, particularly on day 7. Conclusion SBHFRT could lead to more accumulation of dendritic cells and anti-tumor lymphocytes and cytokines in the tumor tissue, and further reduce the aggregation of immunosuppressive lymphocytes and cytokines in the tumor tissue compared with CFRT, and the difference was the most obvious was day 7 after radiation. Hypofractionated radiotherapy combined with immunotherapy may be better for treating NSCLC, as observed on day 7 after radiation.

show abstract

Interleukin-10-regulated tumour tolerance in non-small cell lung cancer

Cited by 80 publications

References 47 publications

Increased expression of the immunosuppressive interleukin-35 in patients with non-small cell lung cancer

Increased expression of the immunosuppressive interleukin-35 in patients with non-small cell lung cancer

Immune-Checkpoint Blockade Opposes CD8+ T-cell Suppression in Human and Murine Cancer

Relationship Between the Invasion of Lymphocytes and Cytokines in the Tumor Microenvironment and the Interval After Single Brachytherapy Hypofractionated Rradiotherapy and Conventional Fractionation Radiotherapy in Non-Small Cell Lung Cancer

Contact Info

Product

Resources

About