PD-1 mRNA expression in peripheral blood cells and its modulation characteristics in cancer patients

Wang, Wei; Ge, Shuping; Wu, Shikai; Song, Santai; Ni, Yanli; Suo, Zhuoyao; Meng, Xiao; Li, Dan; Zhou, Lin; Hao, Rimin; Zhao, Yaowei; Li, Bai; Hou, Li-li; Liu, Bing; Liu, Guangxian

doi:10.18632/oncotarget.15006

Cited by 10 publications

(8 citation statements)

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“…In this study, we focused on the expression of multiple immune checkpoints in the peripheral blood of primary breast and colorectal cancer patients compared with healthy donors. Studies reported that expressions of multiple ICs including PD-1 and CTLA-4 were elevated in the circulation of both PBC 19,20 and CRC. 21 We have recently reported that the promoter demethylation and post-translational histone modifications play a role in the regulation of immune checkpoints in PBC and CRC tumor tissues.…”

Section: Discussionmentioning

confidence: 99%

DNA methylation of immune checkpoints in the peripheral blood of breast and colorectal cancer patients

et al. 2018

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Aberrant expression of immune checkpoints (ICs) in cancer creates an immunosuppressive microenvironment, which supports immune evasion of tumor cells. We have recently reported that epigenetic modifications are critical for ICs expression in the tumor microenvironment (TME) of primary breast cancer (PBC) and colorectal cancer (CRC). Herein, we investigated transcriptomic expression of ICs (PD-1, CTLA-4, LAG-3, TIM-3, TIGIT) and PD-L1 in peripheral blood of PBC and CRC patients, compared to healthy donors (HD). We found that expressions of TIM-3, TIGIT, PD-L1 were significantly upregulated, while LAG-3 expression was downregulated in peripheral blood of PBC and CRC patients. Demethylation enzymes TET2 and TET3 were also upregulated. In addition, promoter DNA methylation status of PD-1 was significantly hypermethylated, while PD-L1 was hypomethylated in PBC and CRC patients. Furthermore, TIGIT was significantly hypomethylated only in CRC patients. Remarkably, promoter methylation status of LAG-3, TIGIT and PD-L1 was in concordance with transcriptomic expression in CRC: the more the hypomethylation, the higher the expression. In comparison, we found that CTLA-4, TIM-3, TIGIT and PD-L1 in PBC, and CTLA-4 in CRC patients were significantly upregulated in peripheral blood, compared with tumor tissues of the same patients. However, demethylation status of all ICs was higher in TT, except for TIGIT in PBC, and CTLA-4 in CRC patients. These data indicate that the underlying mechanisms behind peripheral upregulation of PD-L1 and TIGIT in cancer patients could be due to aberrant promoter methylation profile. Moreover, demethylation inhibitors together with anti-PD-L1/ anti-TIGIT could be a more efficient therapeutic strategy in cancer patients. ARTICLE HISTORY

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Section: Discussionmentioning

confidence: 99%

DNA methylation of immune checkpoints in the peripheral blood of breast and colorectal cancer patients

et al. 2018

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“…Expression of PD-1 on peripheral blood T cells of patients with malignant tumors, including malignant glioma, has previously been reported (29)(30)(31)(32)(33)(34). In most of these previous studies, PD-1 was described as a marker of exhaustion by terminally CD3 þ PD-1 þ T cells from pooled glioma patient PBMCs produce higher levels of IFNg compared to the CD3 þ PD-1 À T cell population after T cell activation.…”

Section: Discussionmentioning

confidence: 94%

Expression of PD-1 by T Cells in Malignant Glioma Patients Reflects Exhaustion and Activation

Davidson

Lee

Hsu

et al. 2019

Clinical Cancer Research

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Purpose: Glioblastoma (GBM) is the most common primary malignant tumor in the central nervous system. Our recent preclinical work has suggested that PD-1/PD-L1 plays an important immunoregulatory role to limit effective antitumor T-cell responses induced by active immunotherapy. However, little is known about the functional role that PD-1 plays on human T lymphocytes in patients with malignant glioma. Experimental Design: In this study, we examined the immune landscape and function of PD-1 expression by T cells from tumor and peripheral blood in patients with malignant glioma. Results: We found several differences between PD-1 þ tumor-infiltrating lymphocytes (TIL) and patient-matched PD-1 þ peripheral blood T lymphocytes. Phenotypically, PD-1 þ TILs exhibited higher expression of markers of activation and exhaustion than peripheral blood PD-1 þ T cells, which instead had increased markers of memory. A comparison of the T-cell receptor variable chain populations revealed decreased diversity in T cells that expressed PD-1, regardless of the location obtained. Functionally, peripheral blood PD-1 þ T cells had a significantly increased proliferative capacity upon activation compared with PD-1 À T cells. Conclusions: Our evidence suggests that PD-1 expression in patients with glioma reflects chronically activated effector T cells that display hallmarks of memory and exhaustion depending on its anatomic location. The decreased diversity in PD-1 þ T cells suggests that the PD-1-expressing population has a narrower range of cognate antigen targets compared with the PD-1 nonexpression population. This information can be used to inform how we interpret immune responses to PD-1-blocking therapies or other immunotherapies.

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“…RNA extraction and cDNA synthesis were performed as previously described. 24 Quantitative real-time PCR was performed to detect PD-1, CD28, CTLA-4, and CD25 mRNA. Forward and reverse primers for PD-1 were 5′-GGTGTGAGGCCATCCACAA-3′ and 5′-CCATTCTGTCGGAGCCTCTG-3′, respectively; those for CD28 were 5′-CGCAGTGGCTCATGCTTGTA-3′ and 5′-TCTCATGCCTCAGCCTCTTG-3′, respectively; those for CTLA-4 were 5′-GCTGACAGCCAGGTGACTGAA-3′ and 5′-TGAGCTCCACCTTGCAGATG-3′, respectively; and those for CD25 were 5′-ATGGCTGCAACCATGGAGAC-3′ and 5′-TCTGTTCCCGGCTTCTTACC-3′, respectively.…”

Section: Methodsmentioning

confidence: 99%

Albumin/globulin ratio is negatively correlated with PD-1 and CD25 mRNA levels in breast cancer patients

Liu¹,

Wang²,

Meng³

et al. 2018

OTT

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BackgroundPrevious studies have demonstrated the prognostic value of globulin (GLB), albumin (ALB), the ALB/GLB ratio (AGR), body mass index (BMI), hemoglobin (Hb), and prognostic nutritional index (PNI) in breast cancer. The underlying mechanism has been investigated by examining the impact of nutritional parameters on T cells, natural killer cells, and dendritic cells, but little is known about their effect on checkpoint molecules.MethodsHere, we investigated the correlation of mRNA expression of programmed cell death protein 1 (PD-1), cluster of differentiation 28 (CD28), cytotoxic T-lymphocyte antigen-4 (CTLA-4), and cluster of differentiation 25 (CD25) with AGR, ALB, GLB, total protein, pre-ALB, Hb, BMI, and PNI in the peripheral blood of breast cancer patients. One hundred and three patients and 21 age- and sex-matched healthy controls were enrolled. Quantitative real-time PCR was used to test relative mRNA expression.ResultsThe results indicated that the mRNA levels of PD-1 and CD25 were 5.2- and 3.3-fold higher in patients with low AGR than in those with high AGR (P < 0.05). The mRNA levels of PD-1 were 3.5-fold higher in patients with high GLB than in those with low GLB (P < 0.05). In addition, breast cancer patients had higher expression levels of PD-1, CD28, CTLA-4, and CD25 mRNA in their peripheral blood compared with healthy volunteers (P < 0.05).ConclusionThese results suggest that AGR is negatively correlated with PD-1 and CD25 mRNA levels, while GLB is positively associated with PD-1 mRNA levels. Nutritional status in breast cancer patients may influence the PD-1 pathway and have implications for the optimization of cancer therapy.

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PD-1 mRNA expression in peripheral blood cells and its modulation characteristics in cancer patients

Cited by 10 publications

References 50 publications

DNA methylation of immune checkpoints in the peripheral blood of breast and colorectal cancer patients

DNA methylation of immune checkpoints in the peripheral blood of breast and colorectal cancer patients

Expression of PD-1 by T Cells in Malignant Glioma Patients Reflects Exhaustion and Activation

Albumin/globulin ratio is negatively correlated with PD-1 and CD25 mRNA levels in breast cancer patients

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