Dual Faces of IFNγ in Cancer Progression: A Role of PD-L1 Induction in the Determination of Pro- and Antitumor Immunity

Mandai, Masaki; Hamanishi, Junzo; Abiko, Kaoru; Matsumura, Noriomi; Baba, Tsukasa; Konishi, Ikuo

doi:10.1158/1078-0432.ccr-16-0224

Cited by 322 publications

(302 citation statements)

References 47 publications

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“…29,30 In addition, since blood endothelial cells express PD-L1, 31 CAS cells may express PD-L1 intrinsically. In vitro experiments using CAS cell lines exhibited PD-L1 expression in cancer cells irrespective of IFNg stimulation.…”

Section: Discussionmentioning

confidence: 99%

Infiltration of PD-1-positive cells in combination with tumor site PD-L1 expression is a positive prognostic factor in cutaneous angiosarcoma

et al. 2016

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Cutaneous angiosarcoma (CAS) is a malignant sarcoma with poor prognosis. Programmed cell death-1 (PD-1)/programmed cell death-1 ligand-1 (PD-L1) expression reflects antitumor immunity, and is associated with patient prognosis in various cancers. The purpose of this study is to investigate the relationship between PD-1/PD-L1 expression and CAS prognosis. CAS cases (n D 106) were immunohistochemically studied for PD-L1 and PD-1 expression, and the correlation with patient prognosis was analyzed. PD-L1 expression was assessed by flow cytometry on three CAS cell lines with or without IFNg stimulation. A total of 30.2% of patients' samples were positive for PD-L1, and 17.9% showed a high infiltration of PD-1-positive cells. Univariate analysis showed a significant relationship between a high infiltration of PD-1-positive cells with tumor site PD-L1 expression and favorable survival in stage 1 patients (p D 0.014, log-rank test). Multivariable Cox-proportional hazard regression analysis also showed that patients with a high infiltration of PD-1-positive cells with tumor site PD-L1 expression were more likely to have favorable survival, after adjustment with possible confounders (hazard ratio (HR) D 0.38, p D 0.021, 95% confidence interval (CI) 0.16-0.86). Immunofluorescence staining of CAS samples revealed that PD-L1-positive cells were adjacent to PD-1-positive cells and/or tumor stroma with high IFNg expression. In vitro stimulation with IFNg increased PD-L1 expression in two out of three established CAS cell lines. Our results suggest that PD-1/PD-L1 expression is related to CAS progression, and the treatment with anti-PD-1 antibodies could be a new therapeutic option for CAS.

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Section: Discussionmentioning

confidence: 99%

Infiltration of PD-1-positive cells in combination with tumor site PD-L1 expression is a positive prognostic factor in cutaneous angiosarcoma

et al. 2016

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“…Considering these results, PD-L1 is involved in dual aspects of immuno-suppression and immuno-stimulation dependent on the current condition. The well-known mechanism for immuno-stimulation is through IFN-γ productions by effector T cells such as tumor-infiltrating lymphocytes (TILs), which, in turn, upregulate PD-L1 expression on tumor cells (13). Interestingly, there were also upregulated genes in the PD-L1-negative group compared with the PD-L1-positive group: B7H3 and B7H4.…”

Section: Discussionmentioning

confidence: 99%

<b>Immune response-associated gene analysis of 1,000 cancer patients using whole-exome sequencing and gene expression profiling—Project </b><b>HOPE— </b>

et al. 2016

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Project HOPE (High-tech Omics-based Patient Evaluation) has been progressing since its implementation in 2014 using whole-exome sequencing (WES) and gene expression profiling (GEP). With the aim of evaluating immune status in cancer patients, a gene panel consisting of 164 immune response-associated genes (56 antigen-presenting cell and T-cell-associated genes, 34 cytokine-and metabolism-associated genes, 47 TNF and TNF receptor superfamily genes, and 27 regulatory T-cell-associated genes) was established, and its expression and mutation status were investigated using 1,000 cancer patient-derived tumors. Regarding WES, sequencing and variant calling were performed using the Ion Proton system. The average number of single-nucleotide variants (SNVs) detected per sample was 183 ± 507, and the number of hypermutators with more than 500 total SNVs was 51 cases. Regarding GEP, seven immune response-associated genes (VTCN1, IL2RA, ULBP2, TREM1, MSR1, TNFSF9 and TNFRSF12A) were more than 2-fold overexpressed compared with normal tissues in more than 2 organs. Specifically, the positive rate of PD-L1 expression in all patients was 25.8%, and PD-L1 expression was significantly upregulated in hypermutators. The simultaneous analyses of WES and GEP based on immune response-associated genes are very intriguing tools to screen cancer patients suitable for immune checkpoint antibody therapy.Cancer immunotherapy has a long history originating from innovating events in the 1970's, such as biological response modifier and hybridoma technology, and moving to the recent renaissance stage in which peptide or dendritic cell (DC)-based vaccines have been applied. Throughout history, even the most powerful modality has not demonstrated a response rate more than 20% in clinical trials, which is referred to as the glass ceiling phenomenon (9, 21).However, since the recent success of immune checkpoint antibodies, such as ipilimumab and nivolumab, reported in metastatic melanoma patients, many ongoing clinical trials have been underway to evaluate their efficacy in various solid cancers other than melanomas (2,8,26,31,33). Specifically, a promising combination therapy of ipilimumab and nivolumab has demonstrated a very high response rate of up to 40% and long-term survival benefit in patients with advanced cancers, including non-small cell lung cancer (18,25,29).

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“…21,23 We next sought to determine whether IFNg also regulates PD-L1 expression in MDSCs. We first analyzed IFNg expression level in the tumor microenvironment.…”

Section: Pd-l1 Expression In Mdscs Depends On Mdsc Anatomic Locationsmentioning

confidence: 99%

“…6,[16][17][18][19][20] It has been shown that PD-L1 is constitutively expressed in various types of tumor cells and regulated by oncogenes. [18][19][20] Furthermore, PD-L1 expression can be upregulated by inflammatory cytokines such as IFNg [20][21][22][23] In addition to expression in tumor cells, PD-L1 is also expressed on subsets of T cells, NK cells, macrophages, myeloid DCs, B cells, epithelial cells and vascular endothelial cells. [24][25][26][27] PD-L1 is notably expressed on mature macrophages, particularly in activated macrophages.…”

Section: Introductionmentioning

confidence: 99%

The expression profiles and regulation of PD-L1 in tumor-induced myeloid-derived suppressor cells

et al. 2016

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Programmed death-ligand 1 (PD-L1) is an inhibitory ligand that binds to PD-1 to suppress T cell activation. PD-L1 is constitutively expressed and inducible in tumor cells, but the expression profiles and regulatory mechanism of PD-L1 in myeloid-derived suppressor cells (MDSCs) are largely unknown. We report that PD-L1 is abundantly expressed in tumor-infiltrating leukocytes in human patients with both microsatellite instable and microsatellite stable colon cancer. About 60% CD11b PD-L1C MDSCs are also significantly higher in tumor-bearing mice than in tumor-free mice. Interestingly, the highest PD-L1C MDSCs were observed in the tumor microenvironment in which 56-71% tumor-infiltrating MDSCs are PD-L1 C in vivo. In contrast, PD-L1 C MDSCs are significantly less in secondary lymphoid organs and peripheral blood as compared to the tumor tissues, whereas bone marrow MDSCs are essentially PD-L1¡ in tumor-bearing mice. IFNg is highly expressed in cells of the tumor tissues and IFNg neutralization significantly decreased PD-L1 C MDSCs in the tumor microenvironment in vivo. However, IFNg-activated pSTAT1 does not bind to the cd274 promoter in MDSCs. Instead, pSTAT1 activates expression of IRF1, IRF5, IRF7 and IRF8 in MDSCs, and only pSTAT1-activated IRF1 binds to a unique IRF-binding sequence element in vitro and chromatin in vivo in the cd274 promoter to activate PD-L1 transcription. Our data determine that PD-L1 is highly expressed in tumor-infiltrating MDSCs and in a lesser degree in lymphoid organs, and the pSTAT1-IRF1 axis regulates PD-L1 expression in MDSCs.

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Dual Faces of IFNγ in Cancer Progression: A Role of PD-L1 Induction in the Determination of Pro- and Antitumor Immunity

Cited by 322 publications

References 47 publications

Infiltration of PD-1-positive cells in combination with tumor site PD-L1 expression is a positive prognostic factor in cutaneous angiosarcoma

Infiltration of PD-1-positive cells in combination with tumor site PD-L1 expression is a positive prognostic factor in cutaneous angiosarcoma

<b>Immune response-associated gene analysis of 1,000 cancer patients using whole-exome sequencing and gene expression profiling—Project </b><b>HOPE— </b>

The expression profiles and regulation of PD-L1 in tumor-induced myeloid-derived suppressor cells

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