Targeting IFNα to tumor by anti-PD-L1 creates feedforward antitumor responses to overcome checkpoint blockade resistance

Liang, Yong; Tang, Haidong; Guo, Jingya; Qiu, Xiangyan; Yang, Zhuo-ya; Ren, Zhenhua; Sun, Zhichen; Bian, Yingjie; Xu, Lily; Xu, Hairong; Shen, Jiming; Han, Yanfei; Dong, Haidong; Peng, Hua; Fu, Yang Xin

doi:10.1038/s41467-018-06890-y

Cited by 68 publications

(61 citation statements)

References 39 publications

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“…Tumor growth inhibition by anti-PD-1 with prior lenvatinib treatment for 1 week was greater than that achieved by anti-PD-1 alone, nontreatment, or nontreatment with prior lenvatinib treatment (S8 Fig). To examine if the response of tumor to lenvatinib was an important component in the response of the tumors to IFN signal activation [23], we divided the mice into two groups according to a mean of tumor sizes after 1 week of lenvatinib treatment: those with relatively lenvatinib-sensitive smaller tumors (LEN-S) and those with relatively larger tumors that were moderately sensitive to lenvatinib (LEN-L). Mice in the LEN-S group that were subsequently treated with anti-PD-1 showed greater tumor reduction than the other treatment groups (S9 Fig).…”

Section: Resultsmentioning

confidence: 99%

Lenvatinib plus anti-PD-1 antibody combination treatment activates CD8+ T cells through reduction of tumor-associated macrophage and activation of the interferon pathway

et al. 2019

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Lenvatinib is a multiple receptor tyrosine kinase inhibitor targeting mainly vascular endothelial growth factor (VEGF) and fibroblast growth factor (FGF) receptors. We investigated the immunomodulatory activities of lenvatinib in the tumor microenvironment and its mechanisms of enhanced antitumor activity when combined with a programmed cell death-1 (PD-1) blockade. Antitumor activity was examined in immunodeficient and immunocompetent mouse tumor models. Single-cell analysis, flow cytometric analysis, and immunohistochemistry were used to analyze immune cell populations and their activation. Gene co-expression network analysis and pathway analysis using RNA sequencing data were used to identify lenvatinib-driven combined activity with anti-PD-1 antibody (anti-PD-1). Lenvatinib showed potent antitumor activity in the immunocompetent tumor microenvironment compared with the immunodeficient tumor microenvironment. Antitumor activity of lenvatinib plus anti-PD-1 was greater than that of either single treatment. Flow cytometric analysis revealed that lenvatinib reduced tumor-associated macrophages (TAMs) and increased the percentage of activated CD8 + T cells secreting interferon (IFN)-γ + and granzyme B (GzmB). Combination treatment further increased the percentage of T cells, especially CD8 + T cells, among CD45 + cells and increased IFN-γ + and GzmB + CD8 + T cells. Transcriptome analyses of tumors resected from treated mice showed that genes specifically regulated by the combination were significantly enriched for type-I IFN signaling. Pretreatment with lenvatinib followed by anti-PD-1 treatment induced significant antitumor activity compared with anti-PD-1 treatment alone. Our findings show that lenvatinib modulates cancer immunity in the tumor microenvironment by reducing TAMs and, when combined with PD-1 blockade, shows enhanced antitumor activity via the IFN signaling pathway. These findings provide a scientific rationale for combination therapy of lenvatinib with PD-1 blockade to improve cancer immunotherapy.

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Section: Resultsmentioning

confidence: 99%

Lenvatinib plus anti-PD-1 antibody combination treatment activates CD8+ T cells through reduction of tumor-associated macrophage and activation of the interferon pathway

et al. 2019

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“…Our study found that high expression of WTAP can reduce T‐cell infiltration and inhibit tumour immunity, which may be supported by the above studies. Liang et al found that IFNs may be an important target for PDL1 immunotherapy, and they also showed that methylation genes are a potential target for this research …”

Section: Discussionmentioning

confidence: 97%

High expression of WTAP leads to poor prognosis of gastric cancer by influencing tumour‐associated T lymphocyte infiltration

Qiao

et al. 2020

J Cellular Molecular Medi

101

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Background: N6-methyladenosine (m6A) methylation, a well-known modification with new epigenetic functions, has been reported to participate in gastric cancer (GC) tumourigenesis, providing novel insights into the molecular pathogenesis of GC.However, the involvement of Wilms' tumour 1-associated protein (WTAP), a key component of m6A methylation, in GC progression is controversial. Here, we investigated the biological role and underlying mechanism of WTAP in GC. Methods: We determined WTAP expression using tissue microarrays and The CancerGenome Atlas (TCGA) data set, which was used to construct co-expression networks by weighted gene co-expression network analysis (WGCNA). Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses were performed by Database for Annotation, Visualization and Integrated Discovery (DAVID). CIBERSORT was used to determine WTAP expression in 22 immune cell types. Results:Wilms' tumour 1-associated protein was highly expressed in GC, which indicated a poor prognosis, and WTAP expression served as an independent predictor of GC survival. By WGCNA, GO, KEGG and core gene survival analyses, we found that high WTAP expression correlated with RNA methylation and that low expression correlated with a high T cell-related immune response. CIBERSORT was used to correlate low WTAP expression with T lymphocyte infiltration. Conclusion: RNA methylation and lymphocyte infiltration are the main causes of high WTAP expression and poor prognosis, respectively. K E Y W O R D S differentially expressed genes, DNA methylation, gastric cancer, N6-methyladenosine (m6A) methylation, WTAP | 4453 LI et aL.

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“…In PDAC tumors from patients and KPC mice, we observed that IL-20 expression significantly correlated with PD-L1 expression. In addition, IL-20 upregulated PD-L1 expression via IFN-α, which is an upstream regulator of PD-L1 produced by some types of cancer cells 40 , 55 . Blocking the activity of IFN-α with an antibody attenuated IL-20-induced PD-L1 expression in KPC tumor cells in vitro, indicating that IL-20 mediated PD-L1 upregulation via IFN-α.…”

Section: Discussionmentioning

confidence: 99%

IL-20 antagonist suppresses PD-L1 expression and prolongs survival in pancreatic cancer models

Pan

Hsu

et al. 2020

Nat Commun

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Pancreatic ductal adenocarcinoma (PDAC) and cancer-associated cachexia (CAC) are multifactorial and characterized by dysregulated inflammatory networks. Whether the proinflammatory cytokine IL-20 is involved in the complex networks of PDAC and CAC remains unclear. Here, we report that elevated IL-20 levels in tumor tissue correlate with poor overall survival in 72 patients with PDAC. In vivo, we establish a transgenic mouse model (KPC) and an orthotopic PDAC model and examine the therapeutic efficacy of an anti-IL-20 monoclonal antibody (7E). Targeting IL-20 not only prolongs survival and attenuates PD-L1 expression in both murine models but also inhibits tumor growth and mitigates M2-like polarization in the orthotopic PDAC model. Combination treatment with 7E and an anti-PD-1 antibody shows better efficacy in inhibiting tumor growth than either treatment alone in the orthotopic PDAC model. Finally, 7E mitigates cachexic symptoms in CAC models. Together, we conclude IL-20 is a critical mediator in PDAC progression.

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Targeting IFNα to tumor by anti-PD-L1 creates feedforward antitumor responses to overcome checkpoint blockade resistance

Cited by 68 publications

References 39 publications

Lenvatinib plus anti-PD-1 antibody combination treatment activates CD8+ T cells through reduction of tumor-associated macrophage and activation of the interferon pathway

Lenvatinib plus anti-PD-1 antibody combination treatment activates CD8+ T cells through reduction of tumor-associated macrophage and activation of the interferon pathway

High expression of WTAP leads to poor prognosis of gastric cancer by influencing tumour‐associated T lymphocyte infiltration

IL-20 antagonist suppresses PD-L1 expression and prolongs survival in pancreatic cancer models

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