scholarly journals Evodiamine suppresses non-small cell lung cancer by elevating CD8+ T cells and downregulating the MUC1-C/PD-L1 axis

2020 ◽  
Vol 39 (1) ◽  
Author(s):  
Ze-Bo Jiang ◽  
Ju-Min Huang ◽  
Ya-Jia Xie ◽  
Yi- Zhong Zhang ◽  
Chan Chang ◽  
...  
Keyword(s):  
Lung Cancer ◽  
T Cells ◽  
Lewis Lung Carcinoma ◽  
Small Cell ◽  
Lewis Lung ◽  
Small Cell Lung ◽  
Programmed Death ◽  
Lewis Lung Carcinoma Model ◽  
Anti Tumor Activity

Abstract Background Accumulating evidence showed that regulating tumor microenvironment plays a vital role in improving antitumor efficiency. Programmed Death Ligand 1 (PD-L1) is expressed in many cancer cell types, while its binding partner Programmed Death 1 (PD1) is expressed in activated T cells and antigen-presenting cells. Whereas, its dysregulation in the microenvironment is poorly understood. In the present study, we confirmed that evodiamine downregulates MUC1-C, resulting in modulating PD-L1 expression in non-small cell lung cancer (NSCLC). Methods Cell viability was measured by MTT assays. Apoptosis, cell cycle and surface PD-L1 expression on NSCLC cells were analyzed by flow cytometry. The expression of MUC1-C and PD-L1 mRNA was measured by real time RT-PCR methods. Protein expression was examined in evodiamine-treated NSCLC cells using immunoblotting or immunofluorescence assays. The effects of evodiamine treatment on NSCLC sensitivity towards T cells were investigated using human peripheral blood mononuclear cells and Jurkat, apoptosis and IL-2 secretion assays. Female H1975 xenograft nude mice were used to assess the effect of evodiamine on tumorigenesis in vivo. Lewis lung carcinoma model was used to investigate the therapeutic effects of combination evodiamine and anti-PD-1 treatment. Results We showed that evodiamine significantly inhibited growth, induced apoptosis and cell cycle arrest at G2 phase of NSCLC cells. Evodiamine suppressed IFN-γ-induced PD-L1 expression in H1975 and H1650. MUC1-C mRNA and protein expression were decreased by evodiamine in NSCLC cells as well. Evodiamine could downregulate the PD-L1 expression and diminish the apoptosis of T cells. It inhibited MUC1-C expression and potentiated CD8+ T cell effector function. Meanwhile, evodiamine showed good anti-tumor activity in H1975 tumor xenograft, which reduced tumor size. Evodiamine exhibited anti-tumor activity by elevation of CD8+ T cells in vivo in Lewis lung carcinoma model. Combination evodiamine and anti-PD-1 mAb treatment enhanced tumor growth control and survival of mice. Conclusions Evodiamine can suppress NSCLC by elevating of CD8+ T cells and downregulating of the MUC1-C/PD-L1 axis. Our findings uncover a novel mechanism of action of evodiamine and indicate that evodiamine represents a potential targeted agent suitable to be combined with immunotherapeutic approaches to treat NSCLC cancer patients. MUC1-C overexpression is common in female, non-smoker, patients with advanced-stage adenocarcinoma.

scholarly journals Combined DLL3-targeted bispecific antibody with PD-1 inhibition is efficient to suppress small cell lung cancer growth

2020 ◽  
Vol 8 (1) ◽  
pp. e000785 ◽  
Author(s):  
Xin Chen ◽  
Norhan Amar ◽  
Yuankui Zhu ◽  
Chunguang Wang ◽  
Chunjiao Xia ◽  
...  
Keyword(s):  
Lung Cancer ◽  
T Cells ◽  
Small Cell Lung Cancer ◽  
Bispecific Antibody ◽  
Small Cell ◽  
Small Cell Lung ◽  
Inhibitory Antibody ◽  
Car T

BackgroundSmall cell lung cancer (SCLC) accounts for 15% of lung cancers, and the primary treatment of this malignancy is chemotherapy and radiotherapy. Delta-like 3 (DLL3) is an attractive target for SCLC immunotherapy since its expression is highly restricted to SCLC with a neglectable appearance on normal adult tissues. In the current study, we aimed to explore the efficacy of DLL3-targeted SCLC immunotherapy via the engagement of T cell.MethodsAs a proof of concept, we constructed DLL3-targeted bispecific antibody and chimeric antigen receptor (CAR)-modified T cells. In vitro and in vivo tumor-suppression activity of these treatments alone or in combination with a Program Death-1 (PD-1) inhibitory antibody was evaluated.ResultsIn vitro studies showed that both DLL3 bispecific antibody and CAR-T efficiently killed DLL3-positive cancer cells, including the native SCLC cell lines H446, H196, H82, and the artificial A431 cells that were forcefully overexpressing DLL3. In vivo studies in xenograft mouse models demonstrated that both bispecific antibody and CAR-T suppressed the tumor growth, and combination therapy with PD-1 inhibitory antibody dramatically improved the efficacy of the DLL3 bispecific antibody, but not the CAR-T cells.ConclusionsOur results demonstrated that DLL3-targeted bispecific antibody plus PD-1 inhibition was effective in controlling SCLC growth.

scholarly journals Discovery of novel non-ATP competitive FGFR1 inhibitors and evaluation of their anti-tumor activity in non-small cell lung cancer in vitro and in vivo

Oncotarget ◽  
2014 ◽  
Vol 5 (12) ◽  
pp. 4543-4553 ◽  
Author(s):  
Jianzhang Wu ◽  
Jiansong Ji ◽  
Bixia Weng ◽  
Peihong Qiu ◽  
Karvannan Kanchana ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Small Cell Lung Cancer ◽  
Cell Lung Cancer ◽  
Small Cell ◽  
Small Cell Lung ◽  
Anti Tumor Activity

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.

278 Phase I clinical trial evaluating the safety of ADP-A2M10 SPEAR T-cells in patients with MAGE-A10+ advanced non-small cell lung cancer

2020 ◽  
Vol 8 (Suppl 3) ◽  
pp. A303-A303
Author(s):  
George Blumenschein ◽  
Siddhartha Devarakonda ◽  
Melissa Johnson ◽  
Victor Moreno ◽  
Justin Gainor ◽  
...  
Keyword(s):  
Lung Cancer ◽  
T Cells ◽  
Antitumor Activity ◽  
Small Cell Lung Cancer ◽  
Dose Level ◽  
Cell Lung Cancer ◽  
Lentiviral Vector ◽  
Small Cell ◽  
Small Cell Lung ◽  
Human Dose

BackgroundADP-A2M10 SPEAR T-cells are genetically engineered autologous T-cells that express a high affinity MAGE-A10-specific T-cell receptor targeting MAGE-A10+tumors in the context of HLA-A*02. This trial is now complete (NCT02592577).MethodsThis first-in-human dose escalation trial utilized a modified 3+3 design to evaluate safety and antitumor activity. Eligible patients (pts) were HLA-A*02+ with advanced non-small cell lung cancer (NSCLC) expressing MAGE-A10. Pts underwent apheresis; T-cells were isolated, transduced with a lentiviral vector containing the TCR targeting MAGE-A10, and expanded. Pts underwent lymphodepletion (LD) with varying doses/schedules of fludarabine (Flu) and cyclophosphamide (Cy) prior to receiving ADP-A2M10. ADP-A2M10 was administered at Dose Level (DL) 1= 0.1×109, DL2 0.5–1.2×109, and DL3/Expansion= 1.2–15×109 transduced cells.ResultsAs of Jan 10, 2020, 11 pts (6 male/5 female) with NSCLC (3 squamous cell, 7 adenocarcinoma, 1 adenosquamous) were treated. Five, 3 and 3 pts received cells at DL1, DL2, and DL3/Expansion, respectively. The most frequently reported adverse events ≥ Grade 3 were lymphopenia (11), leukopenia (9), neutropenia (8), anemia (6), thrombocytopenia (5), and hyponatremia (5). Three pts reported CRS (Grades 1, 2, and 4, respectively). One pt received the highest dose of LD (Flu 30 mg/m2 Day 1 4 and Cy 1800 mg/m2 Day 1–2) prior to a second infusion and had a partial response (PR). This pt subsequently developed aplastic anemia and died. Responses included: 1 pt – PR, 3 pts - stable disease, 2 pts – progressive disease, 1 pt - too early to determine, 4 pts - off-study prior to tumor assessment. SPEAR T-cells were detectable in peripheral blood from pts at each dose level, and in tumor tissue from pts at DL1 and DL3.ConclusionsADP-A2M10 SPEAR T-cells have shown acceptable safety and no evidence of toxicity related to off-target binding or alloreactivity. Given the minimal antitumor activity and the discovery that MAGE-A10 expression frequently overlaps with MAGE-A4 expression, the clinical program has closed. Several trials with SPEAR T-cells targeting MAGE-A4 are ongoing (https://bit.ly/35htsZK).Trial RegistrationNCT02592577Ethics ApprovalThe trial was conducted in accordance with the principles of the Declaration of Helsinki and the International Conference on Harmonization Good Clinical Practice guidelines and was approved by local authorities. An independent ethics committee or institutional review board approved the clinical protocol at each participating center. All the patients provided written informed consent before study entry.

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 Predictive value of 3′-deoxy-3′-18F-fluorothymidine PET in the early response to anti-programmed death-1 therapy in patients with advanced non-small cell lung cancer

2021 ◽  
Vol 9 (7) ◽  
pp. e003079
Author(s):  
Masayuki Sato ◽  
Yukihiro Umeda ◽  
Tetsuya Tsujikawa ◽  
Tetsuya Mori ◽  
Miwa Morikawa ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Small Cell Lung Cancer ◽  
Cell Lung Cancer ◽  
Treatment Initiation ◽  
Early Response ◽  
Small Cell ◽  
Small Cell Lung ◽  
Flt Pet ◽  
Programmed Death ◽  
Programmed Death 1

BackgroundAnti-programmed death-1 (anti-PD-1) therapy has shown clinical success in patients with advanced non-small cell lung cancer (NSCLC). However, it is difficult to evaluate the early response to anti-PD-1 therapy. We determined whether changes in 3′-deoxy-3′-[18F]-fluorothymidine (18F-FLT) PET parameters before and soon after treatment initiation predicted the therapeutic effect of anti-PD-1 antibody.MethodsTwenty-six patients with advanced NSCLC treated with anti-PD-1 antibody were enrolled prospectively and underwent 18F-FLT PET before and at 2 and 6 weeks after treatment initiation. Changes in maximal standardized uptake value (ΔSUVmax), proliferative tumor volume (ΔPTV) and total lesion proliferation (ΔTLP) of the lesions were calculated and evaluated for their associations with the clinical response to therapy.ResultsThe disease control rate was 64%. Patients with non-progressive disease (non-PD) had significantly decreased TLP at 2 weeks, and decreased SUVmax, PTV, and TLP at 6 weeks, compared with those with PD, while three of eight (37.5%) patients who responded had increased TLP from baseline at 2 weeks (ie, pseudoprogression). Among the parameters that changed between baseline and 2 weeks, ΔPTV0-2 and ΔTLP0-2 had the highest accuracy (76.0%) to predict PD. Among the parameters that changed between baseline and 6 weeks, ΔSUVmax0-6, ΔPTV0-6 and ΔTLP0-6 had the highest accuracy (90.9%) to predict PD. ΔTLP0-2 (≥60%, HR 3.41, 95% CI 1.34–8.65, p=0.010) and ΔTLP0-6 (≥50%, HR 31.4, 95% CI 3.55 to 276.7, p=0.0019) were indicators of shorter progression-free survival.ConclusionsChanges in 18F-FLT PET parameters may have value as an early predictive biomarker for the response to anti-PD-1 therapy in patients with NSCLC. However, it should be noted that pseudoprogression was observed in 18F-FLT PET imaging at 2 weeks after treatment initiation.Trial registration numberjRCTs051180147.

scholarly journals Tumour-derived exosomal lncRNA-SOX2OT promotes bone metastasis of non-small cell lung cancer by targeting the miRNA-194-5p/RAC1 signalling axis in osteoclasts

2021 ◽  
Vol 12 (7) ◽  
Author(s):  
Jianjiao Ni ◽  
Xiaofei Zhang ◽  
Juan Li ◽  
Zhiqin Zheng ◽  
Junhua Zhang ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Bone Metastasis ◽  
Small Cell Lung Cancer ◽  
Cell Lung Cancer ◽  
Osteoclast Differentiation ◽  
Small Cell ◽  
Signalling Pathway ◽  
Small Cell Lung

AbstractBone is a frequent metastatic site of non-small cell lung cancer (NSCLC), and bone metastasis (BoM) presents significant challenges for patient survival and quality of life. Osteolytic BoM is characterised by aberrant differentiation and malfunction of osteoclasts through modulation of the TGF-β/pTHrP/RANKL signalling pathway, but its upstream regulatory mechanism is unclear. In this study, we found that lncRNA-SOX2OT was highly accumulated in exosomes derived from the peripheral blood of NSCLC patients with BoM and that patients with higher expression of exosomal lncRNA-SOX2OT had significantly shorter overall survival. Additionally, exosomal lncRNA-SOX2OT derived from NSCLC cells promoted cell invasion and migration in vitro, as well as BoM in vivo. Mechanistically, we discovered that NSCLC cell-derived exosomal lncRNA-SOX2OT modulated osteoclast differentiation and stimulated BoM by targeting the miRNA-194-5p/RAC1 signalling axis and TGF-β/pTHrP/RANKL signalling pathway in osteoclasts. In conclusion, exosomal lncRNA-SOX2OT plays a crucial role in promoting BoM and may serve as a promising prognostic biomarker and treatment target in metastatic NSCLC.

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