Dataset Information

IFN-? down-regulates the PD-1 expression and assist nivolumab in PD-1-blockade effect on CD8+ T-lymphocytes in pancreatic cancer.

ABSTRACT: BACKGROUND:Pancreatic cancer is characterized by a highly immunosuppressive tumor microenvironment and evasion of immune surveillance. Although programmed cell death 1 receptor (PD-1) blockade has achieved certain success in immunogenic cancers, the responses to the PD-1 antibody are not effective or sustained in patients with pancreatic cancer. METHODS:Firstly, PD-1 expressions on peripheral CD8+ T-lymphocytes of patients with pancreatic cancer and healthy donors were measured. In in vitro study, peripheral T-lymphocytes were isolated and treated with nivolumab and/or interferon-?, and next, PD-1-blockade effects, proliferations, cytokine secretions and cytotoxic activities were tested after different treatments. In in vivo study, mice bearing subcutaneous pancreatic cancer cell lines were treated with induced T-lymphocytes and tumor sizes were measured. RESULTS:PD-1 protein expression is increased on peripheral CD8+ T cells in patients with pancreatic ductal adenocarcinoma compared with that in health donor. PD-1 expression on CD8+ T-lymphocytes was decreased by nivolumab in a concentration-dependent manner in vitro. IFN-? could directly down-regulate expression of PD-1 in vitro. Furthermore, the combination therapy of nivolumab and IFN-? resulted in greatest effect of PD-1-blockde (1.73?±?0.78), compared with IFN-? along (18.63?±?0.82) and nivolumab along (13.65?±?1.22). Moreover, the effects of nivolumab plus IFN-? largest promoted the T-lymphocytes function of proliferations, cytokine secretions and cytotoxic activities. Most importantly, T-lymphocytes induced by nivolumab plus IFN-? presented the best repression of tumor growth. CONCLUSIONS:IFN-? plus a PD-1-blockading agent could enhance the immunologic function and might play a crucial role in effective adoptive transfer treatments of pancreatic cancer.

SUBMITTER: Ding G

PROVIDER: S-EPMC6836337 | biostudies-literature | 2019 Nov

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

IFN-γ down-regulates the PD-1 expression and assist nivolumab in PD-1-blockade effect on CD8+ T-lymphocytes in pancreatic cancer.

Ding Guoping G Shen Tao T Yan Chen C Zhang Mingjie M Wu Zhengrong Z Cao Liping L

BMC cancer 20191106 1

<h4>Background</h4>Pancreatic cancer is characterized by a highly immunosuppressive tumor microenvironment and evasion of immune surveillance. Although programmed cell death 1 receptor (PD-1) blockade has achieved certain success in immunogenic cancers, the responses to the PD-1 antibody are not effective or sustained in patients with pancreatic cancer.<h4>Methods</h4>Firstly, PD-1 expressions on peripheral CD8+ T-lymphocytes of patients with pancreatic cancer and healthy donors were measured. I ...[more]

PMID: 31694582

Similar Datasets

Project description:PD-1 immune checkpoint blockade against inhibitory receptors such as receptor programmed cell death-1 (PD-1), has revolutionized cancer treatment. Effective immune reactivity against tumour antigens requires the infiltration and activation of tumour-infiltrating T-cells (TILs). In this context, ligation of the antigen-receptor complex (TCR) in combination with the co-receptor CD28 activates the intracellular mediator AKT (or PKB, protein kinase B) and its downstream targets. PD-1 inhibits the activation of AKT/PKB. Given this, we assessed whether the direct activation of AKT might be effective in activating the immune system to limit the growth of tumors that are resistant to PD-1 checkpoint blockade. We found that the small molecule activator of AKT (SC79) limited growth of a B16 tumor and an EMT-6 syngeneic breast tumor model that are poorly responsive to PD-1 immunotherapy. In the case of B16 tumors, direct AKT activation induced (i) a reduction of suppressor regulatory (Treg) TILs and (ii) an increase in effector CD8+ TILs. SC79 in vivo therapy caused a major increase in the numbers of CD4+ and CD8+ TILs to express interferon-γ (IFN-γ). This effect on IFN-γ expression distinguished responsive from non-responsive anti-tumor responses and could be recapitulated ex vivo with human T-cells. In CD4+FoxP3+Treg TILs, AKT induced IFN-γ expression was accompanied by a loss of suppressor activity, the conversation to CD4+ helper Th1-like TILs and a marked reduction in phospho-SHP2. In CD8+ TILs, we observed an increase in the phospho-activation of PLC-γ. Further, the genetic deletion of the transcription factor T-bet (Tbx21) blocked the increased IFN-γ expression on all subsets while ablating the therapeutic benefits of SC79 on tumor growth. Our study shows that AKT activation therapy acts to induce IFN-γ on CD4 and CD8 TILs that is accompanied by the intra-tumoral conversation of suppressive Tregs into CD4+Th1-like T-cells and augmented CD8 responses.

Project description:Many cancer cells express a major histocompatibility complex class I low/ programmed cell death 1 ligand 1 positive (MHC-Ilo/PD-L1+) cell surface profile. For immunotherapy, there is, thus, an urgent need to restore presentation competence of cancer cells with defects in MHC-I processing/presentation combined with immune interventions that tackle the tumor-initiated PD-L1/PD-1 signaling axis. Using pancreatic ductal adenocarcinoma cells (PDACCs) as a model, we here explored if (and how) expression/processing of tumor antigens via transporters associated with antigen processing (TAP) affects priming of CD8 T cells in PD-1/PD-L1-competent/-deficient mice. We generated tumor antigen-expressing vectors, immunized TAP-competent/-deficient mice and determined de novo primed CD8 T-cell frequencies by flow cytometry. Similarly, we explored the antigenicity and PD-L1/PD-1 sensitivity of PDACCs versus interferon-γ (IFN-γ)-treated PDACCs in PD-1/PD-L1-competent/deficient mice. The IFN-γ-induced effects on gene and cell surface expression profiles were determined by microarrays and flow cytometry. We identified two antigens (cripto-1 and an endogenous leukemia virus-derived gp70) that were expressed in the Endoplasmic Reticulum (ER) of PDACCs and induced CD8 T-cell responses either independent (Cripto-1:Kb/Cr16-24) or dependent (gp70:Kb/p15E) on TAP by DNA immunization. IFN-γ-treatment of PDACCs in vitro upregulated MHC-I- and TAP- but also PD-L1-expression. Mechanistically, PD-L1/PD-1 signaling was superior to the reconstitution of MHC-I presentation competence, as subcutaneously transplanted IFN-γ-treated PDACCs developed tumors in C57BL/6J and PD-L1-/- but not in PD-1-/- mice. Using PDACCs, irradiated at day 3 post-IFN-γ-treatment or PD-L1 knockout PDACCs as vaccines, we could selectively bypass upregulation of PD-L1, preferentially induce TAP-dependent gp70:Kb/p15E-specific CD8 T cells associated with a weakened PD-1+ exhaustion phenotype and reject consecutively injected tumor transplants in C57BL/6J mice. The IFN-γ-treatment protocol is attractive for cell-based immunotherapies, because it restores TAP-dependent antigen processing in cancer cells, facilitates priming of TAP-dependent effector CD8 T-cell responses without additional check point inhibitors and could be combined with genetic vaccines that complement priming of TAP-independent CD8 T cells.

Project description:Preclinical studies suggest that Reed-Sternberg cells exploit the programmed death 1 (PD-1) pathway to evade immune detection. In classic Hodgkin's lymphoma, alterations in chromosome 9p24.1 increase the abundance of the PD-1 ligands, PD-L1 and PD-L2, and promote their induction through Janus kinase (JAK)-signal transducer and activator of transcription (STAT) signaling. We hypothesized that nivolumab, a PD-1-blocking antibody, could inhibit tumor immune evasion in patients with relapsed or refractory Hodgkin's lymphoma.In this ongoing study, 23 patients with relapsed or refractory Hodgkin's lymphoma that had already been heavily treated received nivolumab (at a dose of 3 mg per kilogram of body weight) every 2 weeks until they had a complete response, tumor progression, or excessive toxic effects. Study objectives were measurement of safety and efficacy and assessment of the PDL1 and PDL2 (also called CD274 and PDCD1LG2, respectively) loci and PD-L1 and PD-L2 protein expression.Of the 23 study patients, 78% were enrolled in the study after a relapse following autologous stem-cell transplantation and 78% after a relapse following the receipt of brentuximab vedotin. Drug-related adverse events of any grade and of grade 3 occurred in 78% and 22% of patients, respectively. An objective response was reported in 20 patients (87%), including 17% with a complete response and 70% with a partial response; the remaining 3 patients (13%) had stable disease. The rate of progression-free survival at 24 weeks was 86%; 11 patients were continuing to participate in the study. Reasons for discontinuation included stem-cell transplantation (in 6 patients), disease progression (in 4 patients), and drug toxicity (in 2 patients). Analyses of pretreatment tumor specimens from 10 patients revealed copy-number gains in PDL1 and PDL2 and increased expression of these ligands. Reed-Sternberg cells showed nuclear positivity of phosphorylated STAT3, indicative of active JAK-STAT signaling.Nivolumab had substantial therapeutic activity and an acceptable safety profile in patients with previously heavily treated relapsed or refractory Hodgkin's lymphoma. (Funded by Bristol-Myers Squibb and others; ClinicalTrials.gov number, NCT01592370.).

Dataset Information

IFN-? down-regulates the PD-1 expression and assist nivolumab in PD-1-blockade effect on CD8+ T-lymphocytes in pancreatic cancer.

Publications

IFN-γ down-regulates the PD-1 expression and assist nivolumab in PD-1-blockade effect on CD8+ T-lymphocytes in pancreatic cancer.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets