Highly immunogenic cancer cells require activation of the WNT pathway for immunological escape

Takeuchi, Yoshiko; Tanegashima, Tokiyoshi; Satô, Eiichi; Irie, Takuma; Itahashi, Kota; Kumagai, Shogo; Tada, Yasuko; Togashi, Yosuke; Koyama, Shohei; Akbay, Esra A.; Karasaki, Takahiro; Kataoka, Keisuke; Funaki, Soichiro; Shintani, Yasushi; Nagatomo, Izumi; Kida, Hiroshi; Ishii, Genichiro; Miyoshi, Tomohiro; Aokage, Keiju; Kakimi, Kazuhiro; Ogawa, Seishi; Okumura, Meinoshin; Eto, Masatoshi; Kumanogoh, Atsushi; Tsuboi, Masahiro; Nishikawa, Hiroyoshi

doi:10.1126/sciimmunol.abc6424

Cited by 75 publications

(52 citation statements)

References 55 publications

(75 reference statements)

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“…SPHK1 induces T cell failure and upregulates the PD-1 ligand, creating an immunosuppressive TME (38,39). Similarly, activation of Wnt/β-catenin, MDM2/ p53, and YAP1 signaling leads to immunosuppression, and blocking such signaling can improve the efficacy of ICIs (40)(41)(42).…”

Section: Discussionmentioning

confidence: 99%

Holliday Cross-Recognition Protein HJURP: Association With the Tumor Microenvironment in Hepatocellular Carcinoma and With Patient Prognosis

Luo¹,

Liao²,

Liu³

et al. 2022

Pathol. Oncol. Res.

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Background: Hepatocellular carcinoma is the most common type of primary liver cancer, and it is associated with poor prognosis. It often fails to respond to immunotherapy, highlighting the need to identify genes that are associated with the tumor microenvironment and may be good therapeutic targets. We and others have shown that the Holliday cross-recognition protein HJURP can promote the proliferation, migration, and invasion by hepatocellular carcinoma cells, and that HJURP overexpression is associated with poor survival. Here we explored the potential relationship between HJURP and the tumor microenvironment in hepatocellular carcinoma.Methods: We used the Immuno-Oncology-Biological-Research (IOBR) software package to analyze the potential roles of HJURP in the tumor microenvironment. Using single-cell RNA sequencing data, we identified the cell clusters expressing abundant HJURP, then linked some of these clusters to certain bioprocesses using Gene Set Enrichment Analysis (GSEA). We validated the differential expression of HJURP in tumor-infiltrating CD8+ T cells, sorted by flow cytometry into populations based on the expression level of PD-1. We used weighted gene co-expression network analysis (WGCNA) to identify immunity-related genes whose expression strongly correlated with that of HJURP. The function of these genes was validated based on enrichment in Gene Ontology (GO) terms, and they were used to establish a prognosis prediction model.Results: IOBR analysis suggested that HJURP is significantly related to the immunosuppressive tumor microenvironment and was significantly related to T cells, dendritic cells, and B cells. Based on single-cell RNA sequencing, HJURP was strongly expressed in T cells, erythrocytes, and B cells from normal liver tissues, as well as in CD8+ T cells, dendritic cells, and one cluster of hepatocytes in hepatocellular carcinoma tissues. Malignant hepatocytes strongly expressing HJURP were associated with the downregulation of immune bioprocesses. HJURP expression was significantly higher in CD8+ T cells strongly expressing PD-1 than in those expressing no or intermediate levels of PD1. WGCNA identified two module eigengenes (comprising 397 and 84 genes) related to the tumor microenvironment. We identified 24 hub genes and confirmed that they were related to immune regulation. A prognostic risk score model based on expression of HJURP, PPT1, PML, and CLEC7A showed moderate ability to predict survival.Conclusion:HJURP is associated with tumor-infiltrating immune cells, immune checkpoints, and immune suppression in hepatocellular carcinoma. HJURP-related genes involved in immune responses may be useful for predicting patient prognosis.

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Section: Discussionmentioning

confidence: 99%

Holliday Cross-Recognition Protein HJURP: Association With the Tumor Microenvironment in Hepatocellular Carcinoma and With Patient Prognosis

Luo¹,

Liao²,

Liu³

et al. 2022

Pathol. Oncol. Res.

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“…To the best of our knowledge, this is the first report to comprehensively describe the transcriptomic landscape of tumors (specifically related to PD-1 blockade) among patients with MSI-H/dMMR GI tumors. First, our study revealed that non-responders exhibited enrichment of the EMT, angiogenesis, hypoxia, mTORC1, KRAS, Wnt/β-catenin, TGF-β, and various metabolism-related signaling pathways, all of which have been associated with an immunosuppressive TME (11,(18)(19)(20)(21)(22)(23)(24)(25). On the other hand, the IFN-γ pathway was upregulated in responders, which was in line with previous studies showing that an IFN-γ-related mRNA profile correlated with favorable clinical outcomes with ICIs in several malignancies (26).…”

Section: Discussionmentioning

confidence: 89%

Transcriptomic Profiling of MSI-H/dMMR Gastrointestinal Tumors to Identify Determinants of Responsiveness to Anti–PD-1 Therapy

Chida

Kawazoe

Suzuki

et al. 2022

Clinical Cancer Research

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Purpose: Transcriptomic profiling was performed for microsatellite instability-high (MSI-H)/mismatch repair-deficient (dMMR) gastrointestinal (GI) tumors to determine the predictors of response to PD-1 blockade. Experimental Design: Thirty-six patients with MSI-H/dMMR GI tumors, including gastric cancer, colorectal cancer (CRC), cholangiocarcinoma, small intestine cancer, and pancreatic cancer, being treated with PD-1 blockade were analyzed. We conducted the transcriptomic analysis of GI tumors using RNA sequencing data, including the consensus molecular subtypes (CMS) of CRC. Results: Gene set enrichment analysis (GSEA) demonstrated that non-responders had upregulations of epithelial mesenchymal transition, angiogenesis, hypoxia, mTORC1, TNF-α, KRAS, Wnt/β-catenin, TGF-β, and various metabolism-related signaling pathways. Meanwhile, the IFN-γ pathway was enriched in responders. Based on the leading-edge analysis of GSEA, VEGF-A was significantly correlated with enriched pathways in non-responders. Patients with high VEGF-A expression, compared to those with low expression, had significantly shorter progression-free survival (PFS) (median 4.8 months vs. not reached [NR], P = 0.032) and overall survival (median 11.1 months vs. NR, P = 0.045). Among 13 patients with CRC evaluable for CMS classification, the objective response rate was 100%, 0%, 0%, and 16.7% in CMS1, CMS2, CMS3 and CMS4, respectively. Patients with CMS1 had significantly longer PFS (NR vs. 4.8 months, P = 0.017) than those with CMS2, CMS3, or CMS4. Conclusions: Several transcriptomic features, including CMS classification and related genes, were associated with response to PD-1 blockade in MSI-H/dMMR GI tumors. These findings can help develop predictive biomarkers or combination immunotherapies.

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“…It is notable that most immuno-suppressive genes were negatively related to m7G scores through 33 cancers, such as famous drug targets PD1 (gene: PDCD1 , ≥30 cancers), CTLA4 (gene: CTLA4 , ≥27 cancers) and the next immune checkpoint receptor LAG3 ( Ruffo et al, 2019 ) (gene: LAG3 , ≥27 cancers). Considering the important role of TGF-β1 and Wnt/β-catenin signaling modulating anticancer immune response ( Yoshimura and Muto, 2011 ; Sheng et al, 2015 ; Pai et al, 2017 ; Takeuchi et al, 2021 ), we investigated the correlations of m7G scores and genes involved in those two signaling pathways ( Figures 6A,B ). UBE2D3, APC, SMAD1, BMPR1A, CTNNB1 , and MAP3K7 in TGF-β1 signaling pathway, showed positive correlation with m7G scores through most cancer types (≥30 cancers), while ADAM17, HDAC2, MAML1, CTNNB1, SKP2, MYC and CUL1 in Wnt/β-catenin signaling positively correlated with m7G scores among most cancer types (≥30 cancers).…”

Section: Resultsmentioning

confidence: 99%

Molecular characterization, clinical relevance and immune feature of m7G regulator genes across 33 cancer types

Shen

et al. 2022

Front. Genet.

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Over 170 RNA modifications have been identified after transcriptions, involving in regulation of RNA splicing, processing, translation and decay. Growing evidence has unmasked the crucial role of N6-methyladenosine (m6A) in cancer development and progression, while, as a relative newly found RNA modification, N7-methylguanosine (m7G) is also certified to participate in tumorigenesis via different catalytic machinery from that of m6A. However, system analysis on m7G RNA modification-related regulator genes is lack. In this study, we first investigated the genetic alteration of m7G related regulator genes in 33 cancers, and found mRNA expression levels of most regulator genes were positively correlated with copy number variation (CNV) and negatively correlated with methylation in most cancers. We built a m7G RNA modification model based on the enrichment of the regulator gene scores to evaluate the m7G modification levels in 33 cancers, and investigated the connections of m7G scores to clinical outcomes. Furthermore, we paid close attention to the role of m7G in immunology due to the widely used immune checkpoint blockade therapy. Our results showed the higher m7G scores related to immunosuppression of tumor cells. Further confirmation with phase 3 clinical data with application of anti-PDL1/PDL indicated the impact of m7G modification level on immunotherapy effect. Relevance of m7G regulator genes and drug sensitivity was also evaluated to provide a better treatment choice when treating cancers. In summary, our study uncovered the profile of m7G RNA modification through various cancers, and figured out the connection of m7G modification levels with therapeutical outcomes, providing potential better options of cancer treatment.

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Highly immunogenic cancer cells require activation of the WNT pathway for immunological escape

Abstract: Activation of the WNT pathway allows highly immunogenic cancer cells to escape antitumor immunity and induce cancer progression.

Cited by 75 publications

References 55 publications

Holliday Cross-Recognition Protein HJURP: Association With the Tumor Microenvironment in Hepatocellular Carcinoma and With Patient Prognosis

Holliday Cross-Recognition Protein HJURP: Association With the Tumor Microenvironment in Hepatocellular Carcinoma and With Patient Prognosis

Transcriptomic Profiling of MSI-H/dMMR Gastrointestinal Tumors to Identify Determinants of Responsiveness to Anti–PD-1 Therapy

Molecular characterization, clinical relevance and immune feature of m7G regulator genes across 33 cancer types

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