Oral squamous cell carcinoma suppressed antitumor immunity through induction of PD-L1 expression on tumor-associated macrophages

Jiang, Canhua; Yuan, Fulai; Wang, Jie; Wu, Limeng

doi:10.1016/j.imbio.2016.12.002

Cited by 53 publications

(54 citation statements)

References 31 publications

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“…We have recently reported that a molecular subtype of HNSC with high levels of M1 TAMs overexpresses CD274, the gene encoding PD-L1, a ligand for the CD8+ T cell-expressed immune checkpoint receptor PD-1 51 . This suggests that M1 TAM expression of PD-L1 may contribute to evasion of CD8+ T cell-mediated anti-cancer immunity, as previously reported 48 . To investigate this further, we tested the correlation of OAS2, as a marker of the IFN-responsive/M1 TAM signature, with both ligands for the immune checkpoint receptor PD-1: CD274, the gene encoding PD-L1, and PDCD1LG2, encoding PD-L2.…”

Section: Oas2 Is a Driver Of 'Antiviral' Interferon-modulated Innate supporting

confidence: 84%

“…Both OAS2 and TRIM22 were strongly correlated with M1 macrophage levels across all cancer types. This is consistent with the fact that these pro-inflammatory M1 tumor associated macrophages (TAMs) are activated by IFNγ in response to pathogen infection or cancer, and that M1 macrophage activation or 'polarization' coincides with upregulation of IFN-responsive genes 48 . Interestingly, SP110, a pancancer driver gene of the IFN response subnetwork, is known to regulate macrophage gene expression and differentiation 49,50 .…”

Section: Oas2 Is a Driver Of 'Antiviral' Interferon-modulated Innate supporting

confidence: 76%

“…TAMs include both pro-inflammatory M1 TAMs and anti-inflammatory M2 TAMs, both of which derive from M0 mature macrophages. M1 macrophage activation is stimulated by IFNγ, and is associated with expression of IFN-responsive genes such including OAS2 48,67,68 . Therefore, expression of IFNresponse subnetwork genes may reflect infiltration of M1 TAMs, as part of innate response to cancer.…”

Section: Discussionmentioning

confidence: 99%

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Module analysis captures pancancer genetically and epigenetically deregulated cancer driver genes for smoking and antiviral response

Champion

Brennan

Croonenborghs

et al. 2017

Preprint

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The availability of increasing volumes of multi-omics profiles across many cancers promises to improve our understanding of the regulatory mechanisms underlying cancer. The main challenge is to integrate these multiple levels of omics profiles and especially to analyze them across many cancers. Here we present AMARETTO, an algorithm that addresses both challenges in three steps. First, AMARETTO identifies potential cancer driver genes through integration of copy number, DNA methylation and gene expression data. Then AMARETTO connects these driver genes with coexpressed target genes that they control, defined as regulatory modules. Thirdly, we connect AMARETTO modules identified from different cancer sites into a pancancer network to identify cancer driver genes. Here we applied AMARETTO in a pancancer study comprising eleven cancer sites and confirmed that AMARETTO captures hallmarks of cancer. We also demonstrated that AMARETTO enables the identification of novel pancancer driver genes. In particular, our analysis led to the identification of pancancer driver genes of smoking-induced cancers and 'antiviral' interferon-modulated innate immune response. Software availability:AMARETTO is available as an R package at https://bitbucket.org/gevaertlab/pancanceramaretto Keywords: data fusion, cancer driver gene discovery, module network Highlights:• We present an algorithm for pancancer identification of cancer driver genes based on multiomics data fusion • GPX2 is a novel driver gene in smoking induced cancers and validated using knockdown of GPX2 in the A549 cell line.• OAS2 is a novel driver gene defining cancers with an antiviral signature supported by increased infiltration of tumor-associated macrophages. Research in context:We present an algorithm that combines multiple sources of molecular data to identify novel genes that are involved in cancer development. We applied this algorithm on multiple cancers in a combined fashion and identified a network of pancancer driver genes. We highlighted two genes in detail GPX2 and OAS2. We showed that GPX2 is an important cancer gene in smoking induced cancers, and validated our predictions using experimental data where GPX2 was inactivated in a lung cancer cell line. Similarly we showed that OAS2 is an important cancer driver gene in cancers that show an antiviral signature.

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Section: Oas2 Is a Driver Of 'Antiviral' Interferon-modulated Innate supporting

confidence: 84%

Section: Oas2 Is a Driver Of 'Antiviral' Interferon-modulated Innate supporting

confidence: 76%

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Module analysis captures pancancer genetically and epigenetically deregulated cancer driver genes for smoking and antiviral response

Champion

Brennan

Croonenborghs

et al. 2017

Preprint

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show abstract

“…As cancer stroma of malignant melanoma contains substantial numbers of TAMs that are polarized to M2 phenotypes to maintain an immunosuppressive tumor microenvironment both in mice and humans, and one of the main functions of these TAMs is to produce specific chemokines when stimulated by stromal factors (eg, RANKL, POSTN, etc. ), the immunomodulatory effects of DTIC, ACNU or VCR on M2 macrophages were investigated next, focusing on mRNA expressions of T cell‐related chemokines (CCL17, CCL22, CXCL9, CXCL10, CXCL11) and PD‐L1, which is reported to play an important role in the suppressive function of TAMs . As Figure suggested that the appropriate dose of DTIC, ACNU and VCR for the treatment of M2 macrophages is 1 μg, human M2 macrophages generated from PBMC without or with DTIC, ACNU or VCR at a dose of 1 μg were cultured.…”

Section: Resultsmentioning

confidence: 99%

Cytotoxic antimelanoma drugs suppress the activation of M2 macrophages

Fujimura

Kakizaki

Kambayashi

et al. 2017

Experimental Dermatology

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Together with regulatory T cells (Tregs), tumor-associated macrophages (TAMs) play roles in maintaining the tumor microenvironment. Although cytotoxic antimelanoma drugs such as dacarbazine (DTIC), nimustine hydrochloride (ACNU) and vincristine (VCR) have been used for the treatment of malignant melanoma as adjuvant therapy in Japan, the detailed mechanisms of their immunomodulatory effects are not fully understood. As the majority of TAMs are alternatively activated M2 macrophages that favour tumor development, the aim of this study was to elucidate the immunomodulatory effects of these reagents on human monocyte-derived M2 macrophages. First, mRNA expressions and protein production of immune checkpoint molecules, PD-L1 and chemokines by CD163 + CD206 + M2 macrophages derived from peripheral blood mononuclear cells were investigated to determine the immunomodulatory effects of DTIC, ACNU, and VCR. DTIC and VCR significantly decreased PD-L1 mRNA expression, which was confirmed by flow cytometry. Moreover, the mRNA expression and production of CCL22 were significantly decreased by DTIC, which suggested that DTIC might suppress the recruitment of Tregs in the tumor site. Furthermore, the decreased expression of PD-L1 and production of CCL22 were validated in vivo, using the B16F10 mouse melanoma model, leading to abrogation of the suppressive function of T-cell proliferation. The present report suggests one of the possible antimelanoma mechanisms of DAV combination chemotherapy for melanoma patients.

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“…The tumor microenvironment might be immunosuppressive, while the M2 tumor‐associated macrophage phenotype might contribute to the further development of OSCC 5. In addition, the immunosuppressive effect of OSCC is related to the high expression of the programmed cell death ligand 1 (PD‐L1) 6, 7. PD‐Ll is an important immunological checkpoint protein that binds to programmed cell death protein 1 (PD1) expressed on immune cells, such as activated T cells, by inhibiting the activation and proliferation of T cells 8…”

Section: Introductionmentioning

confidence: 99%

Deubiquitination and stabilization of programmed cell death ligand 1 by ubiquitin‐specific peptidase 9, X‐linked in oral squamous cell carcinoma

Guo

et al. 2018

Cancer Medicine

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BackgroundThe immune checkpoint protein programmed cell death ligand 1 (PD‐L1) binds to PD1 to promote tumor cell escape from the killing effect of the immune system. However, there are few studies on the regulatory mechanisms of PD‐L1 in tumors. Although PD‐L1 has been reported to undergo ubiquitination in some cancers, its regulatory mechanisms in oral squamous cell carcinoma (OSCC) are unclear. Therefore, we aimed to investigate this phenomenon.MethodsWe examined the expression and function of USP9X and PD‐L1 in human oral keratinocytes (HOK) and OSCC cell lines (HN4 and HN30) as the control and relevant cancer cells using western blotting, immunoprecipitation, immunohistochemistry (IHC), T‐cell‐mediated tumor cell killing assay, and liquid chromatography‐mass spectrometry.ResultsProgrammed cell death ligand 1 was highly expressed in OSCC by the regulation of the ubiquitin‐proteasome pathway. Furthermore, we discovered that ubiquitin‐specific peptidase 9, X‐linked (USP9X) could be combined with PD‐L1 to induce its deubiquitination and stabilize its protein expression in OSCC.ConclusionOur data indicate that USP9X deubiquitinates and stabilizes PD‐L1. Suppressing the expression of USP9X blocks tumor cell growth. The results provide a theoretical basis for USP9X as a therapeutic target.

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Oral squamous cell carcinoma suppressed antitumor immunity through induction of PD-L1 expression on tumor-associated macrophages

Cited by 53 publications

References 31 publications

Module analysis captures pancancer genetically and epigenetically deregulated cancer driver genes for smoking and antiviral response

Module analysis captures pancancer genetically and epigenetically deregulated cancer driver genes for smoking and antiviral response

Cytotoxic antimelanoma drugs suppress the activation of M2 macrophages

Deubiquitination and stabilization of programmed cell death ligand 1 by ubiquitin‐specific peptidase 9, X‐linked in oral squamous cell carcinoma

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