Phospho‑STAT1 expression as a potential biomarker for anti‑PD‑1/anti‑PD‑L1 immunotherapy for breast cancer

Nakayama, Yuko; Mimura, Kosaku; Tamaki, Tomoaki; Shiraishi, Kensuke; Kua, Ley‐Fang; Koh, Vivien; Ohmori, Masato; Kimura, Ayako; Inoue, Satoshi; Okayama, Hirokazu; Suzuki, Yoshiyuki; Nakazawa, Tadao; Ichikawa, Daisuke; Kono, Koji

doi:10.3892/ijo.2019.4779

Cited by 44 publications

(51 citation statements)

References 38 publications

(46 reference statements)

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“…Recently, several studies have shown that various transcriptional factors, such as STAT1 [44], STAT3 [45], BRD4 [23], NF-kB [18], PI3K/AKT/mTOR [46], and MEK1/2/ERK1/2 [47], promoted PD-L1 transcription in cancer cells. By carrying out a drug sensitivity assay and several verification experiments, we determined that ITGA2 bound with STAT3 to initiate the transcription of PD-L1 by increasing the phosphorylation level of STAT3 in cancer cells.…”

Section: Discussionmentioning

confidence: 99%

Overexpressed ITGA2 promotes malignant tumor aggression by up-regulating PD-L1 expression through the activation of the STAT3 signaling pathway

Ren

Zhao

Sun

et al. 2019

J Exp Clin Cancer Res

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BackgroundRecent studies have reported that Integrin alpha 2 (ITGA2) plays an essential role in tumor cell proliferation, invasion, metastasis, and angiogenesis. An abnormally expressed ITGA2 correlates with unfavorable prognoses in multiple types of cancer. However, the specific mechanism of how ITGA2 contributes to tumorigenesis remains unclear.MethodsThe GEPIA web tool was used to find the clinical relevance of ITGA2 in cancer, and this significance was verified using Western blotting analysis of paired patient tissues and immunohistochemistry of the pancreatic cancer tissue. Functional assays, such as the MTS assay, colony formation assay, and transwell assay, were used to determine the biological role of ITGA2 in human cancer. The relationship between ITGA2 and programmed death-ligand 1 (PD-L1) was examined using Western blot analysis, RT-qPCR assay, and immunohistochemistry. The protein-protein interaction between ITGA2 and STAT3 was detected via co-immunoprecipitation.ResultsOur study showed that ITGA2 was markedly overexpressed in several malignant tumor cells and clinical tissues. Blocking ITGA2 inhibited the proliferation and invasion ability of cancer cells significantly, whereas overexpressed ITGA2 increased the degree of those processes considerably. Additionally, the RNA-seq assay indicated that ITGA2 transcriptionally regulated the expression of PD-L1 in pancreatic cancer. We also demonstrated that ITGA2 interacted with STAT3 and up-regulated the phosphorylation of STAT3; this interaction might involve the mechanism of ITGA2 inducing PD-L1 expression in cancer cells. Our results suggest that ITGA2 plays a critical role in cancer cell progression and the regulation of PD-L1 by activating the STAT3 pathway.ConclusionsWe identified a novel mechanism by which ITGA2 plays a critical role in modulating cancer immune response by transcriptionally increasing the expression of PD-L1 in cancer cells. Thus, targeting ITGA2 is an effective method to enhance the efficacy of checkpoint immunotherapy against cancer.

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Section: Discussionmentioning

confidence: 99%

Overexpressed ITGA2 promotes malignant tumor aggression by up-regulating PD-L1 expression through the activation of the STAT3 signaling pathway

Ren

Zhao

Sun

et al. 2019

J Exp Clin Cancer Res

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“…The CD8 T effector gene signature was previously established to identify activated T cells such as cytotoxic T lymphocytes (20). The signature scores were calculated by averaging the expression levels of the genes included in each signature (22), excluding HLA-DRA expression values, as these were not available in TCGA RNA-seq data.…”

Section: Methodsmentioning

confidence: 99%

A subset of patients with MSS/MSI‑low‑colorectal cancer showed increased CD8(+) TILs together with up‑regulated IFN‑γ

et al. 2019

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A small subset of patients with proficient mismatch repair (pMMR)/microsatellite stable (MSS)-colorectal cancer (CRC) benefit from immunotherapy with anti-programmed cell death 1 (PD-1)/programmed death ligand 1 (PD-L1) blockade. Therefore, the aim of the current study was to evaluate the immune status of patients with pMMR/microsatellite instability-low (MSI-L)/MSS-CRC and deficient MMR (dMMR)/MSI-high (MSI-H)-CRC in order to identify responders to anti-PD-1/PD-L1 inhibitors. The current study used a dataset downloaded from The Cancer Genome Atlas (TCGA) as well as 219 clinical tissue samples to investigate the infiltrating grade of cluster of differentiation (CD) 4 and CD8 tumor infiltrating lymphocytes (TILs), the expression levels of PD-L1 and PD-L2, the interferon-γ (IFN-γ) and CD8 T effector gene signatures, and the phosphorylated signal transducer and activator of transcription 1 (p-STAT1) status in patients with pMMR/MSI-L/MSS-CRC and dMMR/MSI-H-CRC. Analysis of TCGA dataset revealed that the mRNA expression levels of PD-L1 and PD-L2, the IFN-γ gene signature and the CD8 T effector gene signature were significantly upregulated in MSI-H tumors compared with MSI-L/MSS tumors. Additionally, a subpopulation of patients with upregulation of the IFN-γ and CD8 T effector gene signatures was observed in those with MSI-L/MSS-CRC. Immunohistochemical staining of the clinical samples revealed a subpopulation of patients with pMMR-CRC that were positive for PD-L1 and p-STAT1, and whom had levels of elevated CD8(+) and CD4(+) TILs infiltration similar to those observed in patients with dMMR-CRC. The results obtained in the current study suggested that a subpopulation of patients with MSI-L/MSS-CRC and pMMR-CRC with upregulated IFN-γ and CD8 T effector gene signatures may benefit from immunotherapy with antibodies against PD-1 and PD-L1.

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“…Later, Weichselbaum and coworkers could show a predictive impact of an IFN-related gene signature with regard to the response to chemotherapy and the efficiency of radiation in breast cancer [ 14 ]. In addition, IFN-γ-related gene signatures predicted clinical response to programmed cell death protein 1 (PD-1)/programmed cell death 1 ligand 1 (PD-L1)-inhibiting therapeutic agents in breast cancer [ 15 ] and in other malignancies [ 16 ]. However, studies on the prognostic role of IFN-γ yielded contradictory results [ 17 ].…”

Section: Introductionmentioning

confidence: 99%

Prognostic Significance of Interferon-γ and Its Signaling Pathway in Early Breast Cancer Depends on the Molecular Subtypes

Heimes

Härtner²,

Almstedt

et al. 2020

IJMS

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Interferons are crucial for adaptive immunity and play an important role in the immune landscape of breast cancer. Using microarray-based gene expression analysis, we examined the subtype-specific prognostic significance of interferon-γ (IFN-γ) as a single gene as well as an IFN-γ signature covering the signaling pathway in 461 breast cancer patients. Prognostic significance of IFN-γ, as well as the IFN-γ signature for metastasis-free survival (MFS), were examined using Kaplan–Meier as well as univariate and multivariate Cox regression analyses in the whole cohort and in different molecular subtypes. The independent prognostic significance of IFN-γ as a single gene was limited to basal-like breast cancer (hazard ratio (HR) 2.779, 95% confidence interval (95% CI) 1.117–6.919, p = 0.028). In contrast, the IFN-γ-associated gene signature was an independent prognostic factor in the whole cohort (HR 2.287, 95% CI 1.410–3.633, p < 0.001) as well as in the basal-like (HR 3.458, 95% CI 1.154–10.359, p = 0.027) and luminal B (HR 2.690, 95% CI 1.416–5.112, p = 0.003) molecular subtypes. These results underline the subtype-dependent prognostic influence of the immune system in early breast cancer.

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Phospho‑STAT1 expression as a potential biomarker for anti‑PD‑1/anti‑PD‑L1 immunotherapy for breast cancer

Cited by 44 publications

References 38 publications

Overexpressed ITGA2 promotes malignant tumor aggression by up-regulating PD-L1 expression through the activation of the STAT3 signaling pathway

Overexpressed ITGA2 promotes malignant tumor aggression by up-regulating PD-L1 expression through the activation of the STAT3 signaling pathway

A subset of patients with MSS/MSI‑low‑colorectal cancer showed increased CD8(+) TILs together with up‑regulated IFN‑γ

Prognostic Significance of Interferon-γ and Its Signaling Pathway in Early Breast Cancer Depends on the Molecular Subtypes

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