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PD-1 expression on peripheral blood T-cell subsets correlates with prognosis in non-small cell lung cancer.

ABSTRACT: PD-1 expression in peripheral blood T-cells has been reported in several kinds of cancers, including lung cancer. However, the relationship between PD-1 expression in peripheral blood T-cells and prognosis after treatment with a cancer vaccine has not been reported. To elucidate this relationship, we analyzed PD-1 expression in the peripheral blood T-cells of patients with non-small cell lung cancer. The blood samples used in this study were obtained from patients enrolled in phase II clinical trials of a personalized peptide vaccine. Seventy-eight samples obtained before and after a single vaccination cycle (consisting of six or eight doses) were subjected to the analysis. PD-1 was expressed on lymphocytes in the majority of samples. The relative contents of PD1(+) CD4(+) T-cells against total lymphocytes before and after the vaccination cycle correlated with overall survival (OS) with a high degree of statistical significance (P < 0.0001 and P = 0.0014). A decrease in PD-1(+) CD8(+) T-cells after one cycle of vaccination also correlated with longer OS (P = 0.032). The IgG response to the non-vaccinated peptides suggested that the epitope spreading seemed to occur more frequently in high-PD-1(+) CD4(+) T-cell groups. Enrichment of CD45RA(-) CCR7(-) effector-memory phenotype cells in PD-1(+) T-cells in PBMCs was also shown. These results suggest that PD-1 expression on the peripheral blood T-cell subsets can become a new prognostic marker in non-small cell lung cancer patients treated with personalized peptide vaccination.

SUBMITTER: Waki K

PROVIDER: S-EPMC4462362 | biostudies-literature | 2014 Oct

REPOSITORIES: biostudies-literature

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PD-1 expression on peripheral blood T-cell subsets correlates with prognosis in non-small cell lung cancer.

Waki Kayoko K Yamada Teppei T Yoshiyama Koichi K Terazaki Yasuhiro Y Sakamoto Shinjiro S Matsueda Satoko S Komatsu Nobukazu N Sugawara Shunichi S Takamori Shinzo S Itoh Kyogo K Yamada Akira A

Cancer science 20140923 10

PD-1 expression in peripheral blood T-cells has been reported in several kinds of cancers, including lung cancer. However, the relationship between PD-1 expression in peripheral blood T-cells and prognosis after treatment with a cancer vaccine has not been reported. To elucidate this relationship, we analyzed PD-1 expression in the peripheral blood T-cells of patients with non-small cell lung cancer. The blood samples used in this study were obtained from patients enrolled in phase II clinical t ...[more]

PMID: 25117757

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Project description:BACKGROUND:Anti-programmed cell death 1 (PD-1) antibodies have demonstrated improved overall survival (OS) and progression-free survival (PFS) in a subset of patients with metastatic or locally advanced non-small cell lung cancer (NSCLC). To date, no blood biomarkers have been identified in NSCLC to predict clinical outcomes of treatment with anti-PD-1 antibodies. PATIENT AND METHODS:We performed an analysis of retrospectively registered data of 157 patients with advanced NSCLC treated with anti-PD-1 antibodies at Mayo Clinic in Florida and Rochester. White blood cell count, absolute neutrophil count (ANC), absolute lymphocyte count (ALC), ANC to ALC (ANC: ALC) ratio, absolute eosinophil count, absolute monocyte count (AMC), platelet counts, and myeloid to lymphoid (M:L) ratio at baseline and throughout treatment were assessed. Kaplan-Meier method and Cox proportional hazards model were performed. RESULTS:We treated 146 patients with nivolumab and 11 with pembrolizumab between January 1, 2015 and April 15, 2017. At median follow-up of 20?months, median OS and PFS were 6.0 and 2.6?months, respectively. Higher baseline ANC, AMC, ANC: ALC ratio and M: L ratio correlated with worse clinical outcomes in patients who underwent anti-PD-1 treatment. A baseline ANC: ALC ratio of 5.9 or higher had a significantly increased risk of death (hazard ratio [HR] =1.94; 95% confidence interval [CI], 1.24-3.03; P?=?0.004) and disease progression (HR, 1.65; 95% CI, 1.17-2.34; P?=?0.005) compared with patients with lower ratio. Similarly, a baseline M: L ratio of 11.3 or higher had significantly increased risk of death (HR, 2.5; 95% CI, 1.54-4.05; P?<?0.001), even after a multivariate analysis (HR, 2.31; P?=?0.002), compared to those with lower ratio. CONCLUSIONS:Increased baseline ANC: ALC ratio and M: L ratio before initiation of anti-PD1 antibodies were associated with poor PFS and OS in advanced NSCLC patients. The potential predictive value of these readily available biomarkers might help with risk stratification and treatment strategies. These findings warrant further investigation in a larger, prospective study.

Project description:Background:N6-methyladenosine (m6A) triggers a new layer of epi-transcription. However, the potential noninvasive screening and diagnostic value of peripheral blood m6A for cancer are still unknown. Here, we intend to investigate whether leukocyte m6A can be a novel biomarker for non-small-cell lung cancer (NSCLC). Materials and Methods:Peripheral blood was collected from 119 NSCLC patients and 74 age-matched healthy controls. Total RNA was isolated from leukocytes for m6A measurement, and clinical information of participants was reviewed. The sensitivity, specificity, and area under the curve (AUC) of m6A for cancer diagnosis were evaluated by the receiver-operating characteristic (ROC) curve analysis. Flow cytometry and the Human Protein Atlas (HPA) database were used to characterize m6A in leukocyte differentials. Pearson's correlation was applied to indicate the relationship between m6A level and hematology variables. qPCR and bioinformatic analysis were used to identity the expression of m6A regulators in leukocyte. Results:Leukocyte m6A was significantly elevated in 119 NSCLC patients compared with 74 healthy controls (P<0.001). We did not find significant association between m6A and age or gender. Elevated m6A level in NSCLC was associated with tumor stage (P<0.05) and tumor differentiation (P<0.05), and was significantly reduced after surgery (P<0.01). ROC curve analysis revealed that leukocyte m6A could significantly discriminate patients with lung adenocarcinoma (LUAD) (AUC=0.736, P<0.001) and lung squamous cell carcinoma (LUSC) (AUC=0.963, P<0.001) from healthy individuals. m6A displayed superior sensitivity (100%) and specificity (85.7%) for LUSC than squamous cell carcinoma (SCC) antigen and cytokeratin fragment 211 (Cyfra211). Flow cytometry analysis showed m6A modification was mainly localized on T cells and monocytes among leukocyte differentials. Leukocyte m6A was positively correlated with the number of lymphocytes and negatively correlated with monocytes in NSCLC but not in healthy controls. qPCR and bioinformatic analysis showed that elevated leukocyte m6A in NSCLC was caused by upregulated methyltransferase complex and downregulated FTO and ALKBH5. Conclusion:Leukocyte m6A represents a potential noninvasive biomarker for NSCLC screening, monitoring and diagnosis.

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PD-1 expression on peripheral blood T-cell subsets correlates with prognosis in non-small cell lung cancer.

Publications

PD-1 expression on peripheral blood T-cell subsets correlates with prognosis in non-small cell lung cancer.

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