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1.
Biomedicines ; 9(12)2021 Dec 16.
Article in English | MEDLINE | ID: mdl-34944745

ABSTRACT

Immune checkpoint inhibitors (ICIs) confer remarkable therapeutic benefits to patients with various cancers. However, many patients are non-responders or develop resistance following an initial response to ICIs. There are no reliable biomarkers to predict the therapeutic effect of ICIs. Therefore, this study investigated the clinical implications of plasma levels of soluble anti-programmed death-1 (sPD-1) in patients with cancer treated with ICIs. In total, 22 patients (13 with non-small-cell lung carcinoma, 8 with gastric cancer, and 1 with bladder cancer) were evaluated for sPD-1 concentration using enzyme-linked immunosorbent assays for diagnostic and anti-PD-1 antibody analyses. sPD-1 levels were low before the administration of anti-PD-1 antibodies. After two and four cycles of anti-PD-1 antibody therapy, sPD-1 levels significantly increased compared with pretreatment levels (p = 0.0348 vs. 0.0232). We observed an increased rate of change in plasma sPD-1 concentrations after two and four cycles of anti-PD-1 antibody therapy that significantly correlated with tumor size progression (p = 0.024). sPD-1 may be involved in resistance to anti-PD-1 antibody therapy, suggesting that changes in sPD-1 levels can identify primary ICI non-responders early in treatment. Detailed analysis of each cancer type revealed the potential of sPD-1 as a predictive biomarker of response to ICI treatment in patients with cancer.

2.
Pancreas ; 50(2): 167-175, 2021 02 01.
Article in English | MEDLINE | ID: mdl-33565793

ABSTRACT

OBJECTIVES: The relationship between eosinophils and cancer prognosis is unknown. Therefore, we analyzed the relationship between circulating eosinophils and the survival of stage IIA and IIB pancreatic cancer patients who underwent surgical resection. METHODS: This study included a retrospective cohort of 67 consecutive patients. Patients were categorized into two different groups based on the optimal cutoff for pretreatment levels of each biomarker, according to the receiver operating characteristic curves. RESULTS: The Kaplan-Meier method showed that low eosinophil (P = 0.0403), high neutrophil (P = 0.0066), and high monocyte (P = 0.0003) counts were associated with short overall survival (OS). Low lymphocyte-to-monocyte ratio (P = 0.0194) and eosinophil-to-lymphocyte ratio (ELR) (P = 0.0413) were associated with reduced OS. In multivariate analysis, histological differentiation (P = 0.0014), high neutrophils (P = 0.047), high monocytes (P = 0.029), and low eosinophils (P < 0.0001) were correlated with poorer OS. Histological differentiation (P = 0.033), low lymphocyte-to-monocyte ratio (P = 0.029), and low ELR (P = 0.005) were correlated with poor OS and were significant independent prognostic factors of poor outcomes. CONCLUSIONS: Low eosinophils and low ELR were significant independent prognostic factors of poor outcomes.


Subject(s)
Eosinophils , Lymphocytes , Pancreatectomy , Pancreatic Neoplasms/surgery , Adult , Aged , Aged, 80 and over , Female , Humans , Lymphocyte Count , Male , Middle Aged , Neoplasm Staging , Pancreatectomy/adverse effects , Pancreatectomy/mortality , Pancreatic Neoplasms/blood , Pancreatic Neoplasms/mortality , Pancreatic Neoplasms/pathology , Predictive Value of Tests , Retrospective Studies , Risk Assessment , Risk Factors , Time Factors , Treatment Outcome
3.
Int J Oncol ; 58(1): 57-69, 2021 01.
Article in English | MEDLINE | ID: mdl-33367933

ABSTRACT

Pancreatic cancer is associated with an exceedingly poor prognosis, warranting the development of novel therapeutic strategies and discovery of prognostic predictors. Given that chemoresistance­related molecules are reportedly associated with the poor prognosis of pancreatic cancer, the present study aimed to identify molecules that could be efficacious therapeutic targets for pancreatic cancer. First, 10 patient­derived xenografts (PDXs) were established from patients with pancreatic cancer. Subsequently, after treating tumor tissue generated from the PDXs with standard drugs, next­generation sequencing (NGS) was performed using these tissues. The results of NGS analysis and immunohistochemical analysis on 80 pancreatic cancer tissues revealed that human epididymis protein 4 (HE4) expression in the anticancer drug­treated PDX group was higher than that in the untreated PDXs. In addition, chemoresistance ability was observed in tumor cell lines overexpressing HE4. Furthermore, Kaplan­Meier analysis of tumor tissues from 80 patients with pancreatic cancer was performed and it was found that patients with a high HE4 expression level had a poor survival rate compared with those who had a low HE4 expression level. Multivariate analysis also indicated the high expression level of HE4 was an independent poor prognostic biomarker. Thus, it was concluded that high gene and protein expression levels of HE4 mediate chemoresistance and are independent prognostic factors for pancreatic cancer.


Subject(s)
Antineoplastic Agents/pharmacology , Biomarkers, Tumor/metabolism , Drug Resistance, Neoplasm/genetics , Pancreatic Neoplasms/etiology , WAP Four-Disulfide Core Domain Protein 2/metabolism , Aged , Animals , Antineoplastic Agents/therapeutic use , Biomarkers, Tumor/analysis , Biomarkers, Tumor/genetics , Cell Line, Tumor , Female , Humans , Kaplan-Meier Estimate , Male , Mice , Middle Aged , Pancreas/pathology , Pancreatic Neoplasms/drug therapy , Pancreatic Neoplasms/genetics , Pancreatic Neoplasms/mortality , Prognosis , RNA, Messenger/analysis , RNA, Messenger/metabolism , WAP Four-Disulfide Core Domain Protein 2/analysis , WAP Four-Disulfide Core Domain Protein 2/genetics , Xenograft Model Antitumor Assays
4.
Cancer Immunol Immunother ; 70(2): 337-348, 2021 Feb.
Article in English | MEDLINE | ID: mdl-32757055

ABSTRACT

PURPOSE: Targeting of anti-programmed cell death protein-1 (PD-1) and anti-programmed death-ligand 1 (PD-L1) is a standard therapeutic strategy for various cancers. The aim of the present study was to investigate the prognostic effect of pretreatment PD-L1 expression levels in peripheral blood mononuclear cell (PBMC) subsets for patients with several cancer types receiving anti-PD-1 blockade therapies. PATIENTS AND METHODS: Thirty-two patients undergoing anti-PD-L1 blockade therapy, including 15 with non-small cell lung cancer, 14 with gastric cancer, 1 with melanoma, 1 with parotid cancer, and 1 with bladder cancer, were recruited for the present study. PD-L1 expression levels in CD3+, CD4+, CD8+, CD45RA+ and CCR7+ T cells; CD20+ B cells; CD14+ and CD16+ monocytes were measured via flow cytometry before treatment. The percentages of PD-L1+ cells in respective PBMC subsets were compared with respect to different clinicopathological conditions and the association with overall survival (OS) was assessed. RESULTS: The percentages of PD-L1+ with CD3+, CD4+ and CD8+ T cells including naïve and memory T cell subsets, or CD20+ B cells during pretreatment were not markedly correlated with the OS of patients (p > 0.05); however, the percentage of the PD-L1+ CD14+ monocyte subset was significantly correlated with OS (p = 0.0426). CONCLUSION: Increase in pretreatment expression levels of PD-L1 on CD14+ monocytes is associated with the OS of patients treated with immune checkpoint inhibitors. Further evaluation of large sample size and each specific cancer type might clarify the predictive role of PBMC in patients.


Subject(s)
B7-H1 Antigen/drug effects , Immune Checkpoint Inhibitors/adverse effects , Lipopolysaccharide Receptors/drug effects , Monocytes/metabolism , B7-H1 Antigen/adverse effects , Female , Humans , Male , Survival Analysis
5.
Oncol Rep ; 44(1): 252-262, 2020 07.
Article in English | MEDLINE | ID: mdl-32627041

ABSTRACT

Pancreatic cancer has extremely poor prognosis, warranting the discovery of novel therapeutic and prognostic markers. The expression of polymeric immunoglobulin receptor (pIgR), a key component of the mucosal immune system, is increased in several cancers. However, its clinical relevance in pancreatic cancer remains unclear. In the present study, the prognostic value of pIgR in pancreatic cancer patients after surgical resection was assessed and it was determined that the expression of pIgR was correlated with poor prognosis. Ten pancreatic cancer patient­derived xenograft (PDX) lines were established, followed by next­generation sequencing of tumor tissues from these lines after standard chemotherapy. Immunohistochemical analysis of chemoresistance­related molecules using 77 pancreatic cancer tissues was also performed. The expression of pIgR mRNA in the PDX group treated with anticancer drugs was higher than in the untreated group. High pIgR expression in tissue specimens from 77 pancreatic cancer patients was significantly associated with poor prognosis and was revealed to be an independent prognostic factor, predicting poor outcomes. High pIgR mRNA and protein levels were independent prognostic factors, indicating that pIgR could be a novel predictor for poor prognosis of pancreatic cancer patients.


Subject(s)
Antineoplastic Agents/therapeutic use , Drug Resistance, Neoplasm , Pancreatic Neoplasms/drug therapy , Receptors, Polymeric Immunoglobulin/genetics , Receptors, Polymeric Immunoglobulin/metabolism , Aged , Animals , Antineoplastic Agents/pharmacology , Biomarkers, Tumor/genetics , Biomarkers, Tumor/metabolism , Cell Line, Tumor , Female , Gene Expression Profiling , High-Throughput Nucleotide Sequencing , Humans , Male , Mice , Middle Aged , Neoplasm Transplantation , Pancreatic Neoplasms/genetics , Pancreatic Neoplasms/metabolism , Prognosis , Survival Analysis
6.
PLoS One ; 15(1): e0226707, 2020.
Article in English | MEDLINE | ID: mdl-31923206

ABSTRACT

Pancreatic cancer has an extremely poor prognosis, and identification of novel predictors of therapeutic efficacy and prognosis is urgently needed. Chemoresistance-related molecules are correlated with poor prognosis and may be effective targets for cancer treatment. Here, we aimed to identify novel molecules correlated with chemoresistance and poor prognosis in pancreatic cancer. We established 10 patient-derived xenograft (PDX) lines from patients with pancreatic cancer and performed next-generation sequencing (NGS) of tumor tissues from PDXs after treatment with standard drugs. We established a gene-transferred tumor cell line to express chemoresistance-related molecules and analyzed the chemoresistance of the established cell line against standard drugs. Finally, we performed immunohistochemical (IHC) analysis of chemoresistance-related molecules using 80 pancreatic cancer tissues. From NGS analysis, we identified olfactomedin-4 (OLFM4) as having high expression in the PDX group treated with anticancer drugs. In IHC analysis, OLFM4 expression was also high in PDXs administered anticancer drugs compared with that in untreated PDXs. Chemoresistance was observed by in vitro analysis of tumor cell lines with forced expression of OLFM4. In an assessment of tissue specimens from 80 patients with pancreatic cancer, Kaplan-Meier analysis showed that patients in the low OLFM4 expression group had a better survival rate than patients in the high OLFM4 expression group. Additionally, multivariate analysis showed that high expression of OLFM4 was an independent prognostic factor predicting poor outcomes. Overall, our study revealed that high expression of OLFM4 was involved in chemoresistance and was an independent prognostic factor in pancreatic cancer. OLFM4 may be a candidate therapeutic target in pancreatic cancer.


Subject(s)
Drug Resistance, Neoplasm/genetics , Gene Expression Regulation, Neoplastic , Granulocyte Colony-Stimulating Factor/genetics , Pancreatic Neoplasms/diagnosis , Pancreatic Neoplasms/genetics , Animals , Cell Transformation, Neoplastic , HeLa Cells , Humans , Kaplan-Meier Estimate , Mice , Prognosis
7.
Anticancer Res ; 39(9): 5195-5201, 2019 Sep.
Article in English | MEDLINE | ID: mdl-31519633

ABSTRACT

BACKGROUND/AIM: Cancer immune therapy by immune checkpoint inhibitors (ICIs) is a promising therapeutic strategy for various cancer types. Among ICIs, anti-programmed cell death protein-1 (PD1) and anti-programmed death-ligand 1 (PD-L1) antibodies have shown a remarkable clinical benefit. The present study aimed to address the functional and clinical significance of serum levels of soluble PD-L1 (sPD-L1) in patients. MATERIALS AND METHODS: A total of 21 patients, 11 with NSCLC, nine with gastric cancer and one with bladder cancer, who underwent anti-PD-1 therapy were evaluated for sPD-L1 concentration by ELISA analyses at diagnosis and after treatment. RESULTS: Pretreatment levels of sPD-L1 in patients who received ICIs were not remarkably correlated with the overall survival of these patients (r=0.3394, p=0.1323). Reduction of plasma sPD-L1 level was significantly correlated with tumor regression in patients administered four cycles of treatment (p<0.05). CONCLUSION: sPD-L1 might be derived and secreted from tumors and might be useful to identify primary responders to ICIs at a relatively early treatment timepoint.


Subject(s)
Antineoplastic Agents, Immunological/therapeutic use , B7-H1 Antigen/blood , Biomarkers, Tumor , Lung Neoplasms/blood , Lung Neoplasms/pathology , Stomach Neoplasms/blood , Stomach Neoplasms/pathology , Aged , Aged, 80 and over , Antineoplastic Agents, Immunological/pharmacology , B7-H1 Antigen/antagonists & inhibitors , Disease Progression , Female , Humans , Lung Neoplasms/drug therapy , Male , Middle Aged , Neoplasm Staging , Prognosis , Retrospective Studies , Stomach Neoplasms/drug therapy , Treatment Outcome
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