Stroma remodeling and reduced cell division define durable response to PD-1 blockade in melanoma

Galvani, Elena; Mundra, Piyushkumar A.; Valpione, Sara; García-Martínez, Pablo; Smith, Matthew; Greenall, Jonathan; Thakur, Rohit; Helmink, Beth A.; Andrews, Miles C.; Boon, Louis; Chester, Christopher; Gremel, Gabriela; Hogan, Kate; Mandal, Amit Kumar; Zeng, Kang; Banyard, Antonia; Ashton, Garry; Cook, Martin; Lorigan, Paul; Wargo, Jennifer A.; Dhomen, Nathalie; Marais, Richard

doi:10.1038/s41467-020-14632-2

Cited by 28 publications

(28 citation statements)

References 40 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…GO203, targeting MUC1-C, can suppress PD-L1 expression of NSCLC and breast cancer, and induces effectors of innate and adaptive immunity, resulting in improve anticancer effects [31] We determined that evodiamine can block PD-L1 expression on mRNA and protein levels, perhaps through inhibiting the MUC1-C. Silencing MUC1-C in H1975 decreases apoptosis following evodiamine treatment. Currently, several preclinical and clinical trials for the combination of other therapy with immune inhibitors in the treatment patients reveal biomarkers of response and resistance to anti-PD-1 monotherapy and combined anti-CTLA-4 and anti-PD-1 immunotherapy, significantly improve the anti-tumor effect [6,[58][59][60][61]. Collectively, the combination of evodiamine and PD-1 mAb treatment enhance anti-cancer and survival in a Lewis lung carcinoma model.…”

Section: Discussionmentioning

confidence: 99%

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

Jiang

Huang

Xie

et al. 2020

J Exp Clin Cancer Res

View full text Add to dashboard Cite

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.

show abstract

Section: Discussionmentioning

confidence: 99%

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

Jiang

Huang

Xie

et al. 2020

J Exp Clin Cancer Res

View full text Add to dashboard Cite

show abstract

“…The interaction between tumor cells and CAFs may cause treatment failure (Errarte et al, 2020 ). CAFs promote tumor matrix deposition and remodeling in the TME (Sahai et al, 2020 ), help cancer cells evade immune surveillance (De Jaeghere et al, 2019 ), and achieve resistance to immunotherapy (Galvani et al, 2020 ). A study showed that the extracellular matrix could reduce the effectiveness of immune checkpoint blockers (Wang et al, 2018 ).…”

Section: Discussionmentioning

confidence: 99%

Identification of a Gene Signature for Renal Cell Carcinoma–Associated Fibroblasts Mediating Cancer Progression and Affecting Prognosis

Liu

Chen

Zhan

et al. 2021

Front. Cell Dev. Biol.

View full text Add to dashboard Cite

Background: Cancer-associated fibroblasts (CAFs) are mainly involved in cancer progression and treatment failure. However, the specific signature of CAFs and their related clinicopathological parameters in renal cell carcinoma (RCC) remain unclear. Here, methods to recognize gene signatures were employed to roughly assess the infiltration of CAFs in RCC, based on the data from The Cancer Genome Atlas (TCGA). Weighted Gene Coexpression Network Analysis (WGCNA) was used to cluster transcriptomes and correlate with CAFs to identify the gene signature. Single-cell and cell line sequencing data were used to verify the expression specificity of the gene signature in CAFs. The gene signature was used to evaluate the infiltration of CAFs in each sample, and the clinical significance of each key gene in the gene signature and CAFs was analyzed. We observed that the CAF infiltration was higher in kidney cancer and advanced tumor stage and grade than in normal tissues. The seven key genes of the CAF gene signature identified using WGCNA showed high expression of CAF-related characteristics in the cell clustering landscape and fibroblast cell lines; these genes were found to be associated with extracellular matrix function, collagen synthesis, cell surface interaction, and adhesion. The high CAF infiltration and the key genes were verified from the TCGA and Gene Expression Omnibus data related to the advanced grade, advanced stage, and poor prognosis of RCC. In summary, our findings indicate that the clinically significant gene signature may serve as a potential biomarker of CAFs in RCC, and the infiltration of CAFs is associated with the pathological grade, stage, and prognosis of RCC.

show abstract

“…The interaction between tumor cells and CAFs may be the cause of treatment failure [24]. CAFs promote tumor matrix deposition and remodeling in the TME [25], help cancer cells evade immune surveillance [26], and achieve resistance to immunotherapy [27]. A study showed that the extracellular matrix can reduce the effectiveness of immune checkpoint blockers [28].…”

Section: Discussionmentioning

confidence: 99%

Identification of Gene Signature for Renal Cell Carcinoma-Associated Fibroblasts Mediating Cancer Progression and Affecting Prognosis

et al. 2020

View full text Add to dashboard Cite

Background: Cancer-associated broblasts (CAFs) are most abundant in stroma and are critically involved in cancer progression. However, the speci c signature of CAFs and related clinicopathological parameters in renal cell carcinoma (RCC) remain unclear. Methods: In this work, methods using recognized gene signatures were employed to roughly assess the in ltration level of the stroma and CAFs in RCC based on the data in The Cancer Genome Atlas. Weighted gene co-expression network analysis (WGCNA) was used to cluster transcriptomes and correlate with CAFs to identify speci c markers. A comparison of broblast versus urothelial carcinoma cell lines and correlation with previously reported CAF markers were performed to demonstrate the speci c expressed of the gene signature. The gene signature was used to compare broblast in ltration of each sample through single sample gene set enrichment analysis, and the clinical signi cance of broblasts was analyzed via Cox risk assessment and the chi-square test. Finally, we used validation data to verify the clinical signi cance of the broblast gene signature in RCC. Results: Roughly calculated tumor matrix and CAF levels were signi cantly higher in kidney cancer than in normal tissues. More than 85% of broblast-speci c markers identi ed by WGCNA were consistent with markers obtained via single-cell sequencing. These markers were more highly expressed in broblast cell lines and were signi cantly correlated with canonical CAFs makers. Data validation also showed that CAFs were signi cant correlation with survival and pathological grade. Conclusions: In summary, our ndings indicate that the gene signature potentially serves as a biomarker of CAFs in RCC and that in ltration of broblasts in RCC is an independent prognostic factor associated with pathological grade and stage of tumor. The ability to recognize speci c CAF markers using WGCNA is comparable to single-cell sequencing.

show abstract

Stroma remodeling and reduced cell division define durable response to PD-1 blockade in melanoma

Cited by 28 publications

References 40 publications

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

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

Identification of a Gene Signature for Renal Cell Carcinoma–Associated Fibroblasts Mediating Cancer Progression and Affecting Prognosis

Identification of Gene Signature for Renal Cell Carcinoma-Associated Fibroblasts Mediating Cancer Progression and Affecting Prognosis

Contact Info

Product

Resources

About