Abstract
BackgroundThe purpose of the present study was to explore novel biomarkers that can predict the clinical outcome of patients before treatment or during vaccination. These would be useful for the selection of appropriate patients who would be expected to exhibit better treatment outcomes from vaccination, and for facilitating the development of cancer vaccine treatments.MethodsFrom a single-arm, non-randomized, human leukocyte antigen (HLA)-A-status-blind phase II trial of a vaccine treatment using three HLA-A*2402-restricted peptides for advanced pancreatic cancer (PC), we obtained peripheral blood samples from 36 patients of an HLA-A*2402-matched group and 27 patients of an HLA-A*2402-unmatched group.ResultsMultivariate analysis (HR = 2.546; 95% CI = 1.138 to 5.765; p = 0.0231) and log-rank test (p = 0.0036) showed that a high expression level of programmed death-1 (PD-1) on CD4+ T cells was a negative predictive biomarker of overall survival in the HLA-A*2402-matched group . Moreover, a high expression level of PD-1 on CD4+ T cells was a negative predictor for the induction of cytotoxic T lymphocytes (p = 0.0007). After treatment, we found that the upregulation of PD-1 and T cell immunoglobulin mucin-3 (Tim-3) expression on CD4+ and CD8+ T cells was significantly associated with a poor clinical outcome in the HLA-A*2402-matched group (p = 0.0330, 0.0282, 0.0046, and 0.0068, respectively). In contrast, there was no significant difference for these factors in the HLA-A*2402-unmatched group.ConclusionsOur results indicate that the upregulation of PD-1 and Tim-3 expression on CD4+ and CD8+ T cells may restrict T cell responses in advanced PC patients; therefore, combination immunotherapy with blockade of PD-1 and Tim-3 to restore T cell responses may be a potential therapeutic approach for advanced PC patients.Trial registrationClinical-Trail-Registration: UMIN000008082.
Highlights
The purpose of the present study was to explore novel biomarkers that can predict the clinical outcome of patients before treatment or during vaccination
To explore predictive biomarkers for this vaccine therapy, we analyzed the parameters of age, gender, disease stage, hemoglobin (Hb), neutrophil-lymphocyte ratio (NLR), carcinoembryonic antigen (CEA), carbohydrate antigen 19-9 (CA19-9), IL-6, programmed death-1 (PD-1)+ CD4+ T cells, Tim3+ CD4+ T cells, PD-1+ CD8+ T cells, T cell immunoglobulin mucin-3 (Tim-3)+ CD8+ T cells, Regulatory T cells (Tregs), and myeloid-derived suppressor cells (MDSCs) in the human leukocyte antigen (HLA)-A*2402-matched group
We found that the upregulation of PD-1 and Tim-3 expression on CD4+ T cells was significantly associated with a poor prognosis in the HLA-A*2402matched group (p = 0.0330 and p = 0.0282, respectively; Fig. 3b and 3e)
Summary
The purpose of the present study was to explore novel biomarkers that can predict the clinical outcome of patients before treatment or during vaccination. Recent advances in cancer immunotherapies, such as immune checkpoint inhibitors, have shown some durable clinical responses in patients with various types of advanced cancers [8, 9]. Since their clinical efficacy remains limited, active immunotherapies using tumor-associated antigen (TAA)-derived epitope peptides, which can induce tumor-specific cytotoxic T lymphocytes (CTLs) in vivo, should be developed. There is a desperate need to identify predictive biomarkers that can enable, prior to treatment, the selection of patients who are likely to respond well and effectively to epitope peptides that induce specific CTLs [15,16,17,18,19]
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