Anti PD-L1 Monoclonal Antibody Research Articles

Osteoclasts Promote Immune Suppressive Microenvironment in Multiple Myeloma: Therapeutic Implication

Purpose: The number and activity of osteoclasts (OCs) are strongly enhanced by myeloma cells, leading to significant bone lesion in patients with multiple myeloma (MM). Mechanisms remain elusive whether myeloma-supporting OCs also induce suppressive immune bone marrow (BM) microenvironment.Methods: We examined if OCs could modulate T cell-mediated anti-MM immunity; Inhibitory immune molecules expression during osteoclastogenesis; The impact of APRIL on PDL1 expression in MM and the pathway; The impact of Anti-CD38 mAb on osteoclastogenesis and T cell response;Results: Here, we first show that OCs significantly protect MM cells against T cell-mediated cytotoxicity via direct inhibition of proliferating CD4+and CD8+ T cells. The immune checkpoint molecules PDL1, Galectin-9, HVEM, and CD200, as well as T cell metabolism regulators indoleamine 2, 3-dioxygenase (IDO) and CD38 are significantly up-regulated during osteoclastogenesis. Importantly, levels of these molecules, except CD38, are higher in OCs than MM cells. Anti-PDL1 monoclonal antibody and IDO inhibitor partly overcome OC-inhibited T cell responses against MM cells, confirming their roles in OC-suppressed MM cell lysis by cytotoxic T cells. In addition, Galectin-9 and a proliferation-induced ligand (APRIL), mainly secreted by OCs, are significantly up-regulated during osteoclastogenesis. Galectin-9 specifically induces apoptosis of T cells while sparing monocytes and MM cells. APRIL induces PDL1 expression in MM cells, providing additional immune inhibition by OCs. Moreover, CD38 is significantly up-regulated during osteoclastogenesis. When targeted by an anti-CD38 monoclonal antibody, suppressive T cell function by OCs is alleviated, associated with down-regulation of HVEM and IDO.Conclusion: Taken together, these results define expression of multiple immune proteins and cytokines in OCs essential for suppressive MM BM milieu. These results further support combination of targeting these molecules to improve anti-MM immunity. DisclosuresAnderson:Celgene: Membership on an entity's Board of Directors or advisory committees; C4 Therapeutics: Equity Ownership; Gilead: Membership on an entity's Board of Directors or advisory committees; Acetylon: Equity Ownership; Oncoprep: Equity Ownership; Millennuim: Membership on an entity's Board of Directors or advisory committees; Oncoprep: Equity Ownership; Gilead: Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees; Acetylon: Equity Ownership; Millennuim: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; C4 Therapeutics: Equity Ownership; Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees.

Nivolumab in second-line treatment of squamous non-small cell lung cancer.

The treatment of non-small cell lung cancer (NSCLC) is changing dramatically in the last period, considering both non-squamous and squamous disease. In the last five years, the identification of different molecular predictive biomarker (e.g., EGFR, ALK e ROS1) and the utilize of new chemotherapy agents associated or not with antiangiogenics agents (e.g., bevacizumab and nintedanib), allowed the improvement of survival and related responses to these treatments. However, these advances, did not allow an improvement of the same endpoints in the management of NSCLC with squamous cell histology (SCC), where until very recently, docetaxel in monotherapy remained as a corner stone treatment for the second line, although associated with an unfavorable toxicity profile. In recent years, the improvement knowledge of mechanisms of immune response in patients suffering from solid tumors, and especially lung cancer, allowed the identification of different anti-PD1 and anti-PDL1 monoclonal antibodies (e.g., atezolizumab, avelumab, nivolumab, pembrolizumab) able to improved survival and response when used in second-line setting. In this review, we report the evidences of nivolumab in NSCLC with squamous histology, through the discussion of data related to phase I, II and III published and searchable via Medline/PubMed.

Abstract 3943: Baseline LDH serum level as predictive value of activity in patients treated with anti PD-1 and PDL-1 monoclonal antibodies

Abstract BACKGROUND: Lactate dehydrogenase (LDH) is a key enzyme in the glycolytic metabolism, especially in anaerobic condition. High serum levels at baseline seem to be a negative prognostic marker in many tumor types, as well a negative predictive marker for response to treatment with anti CTL4 antibodies(Ipilimumab)in Malignant Melanoma. Recently, the treatment of several advanced tumors with anti PD-1 or PDL-1 monoclonal antibodies (mAbs) showed better outcome in comparison to Ipilimumab. However, biomarkers for a proper selection of responding patients is not yet available. The aim of this study is to correlate LDH serum level at baseline with clinical outcome in patients (pts) with advanced solid tumors treated with anti PDL-1 and anti PD-1 mAbs. MATERIAL AND METHODS: We evaluated baseline LDH serum level in 145 pts affected by advanced solid tumors, treated at our Institute with anti PDL-1 and anti PD-1 mAbs. The rate of clinical responses and progression free survival (PFS) were related to normal or elevated baseline LDH serum level. We stratified the pts in 4 groups: normal value (group A),up to 1.5 x ULN (group B); < 2 > 1.5 x ULN (Group C); > 2 x ULN (Group D). We defined as disease control (DC) any complete (CR) and partial response (PR) or stable disease (SD) lasting > 3 months. Correlation between LDH serum levels and DC was assessed by Fisher's exact test; PFS was estimated using the Kaplan-Meier method. RESULTS: We evaluated a heterogeneous population of 145 patients: 73 pts with lung cancer (50.3%; 67 NSCLC, 6 SCLC); 32 pts with Melanoma (22%) and 40 pts (27.6%) with other solid tumors (8 urothelial, 7 biliary tract, 6 mesothelioma, 4 head and neck, 4 sarcoma, 3 gastric, 3 colon, 2 RCC, 1 thyroid, 1 ovarian, 1 HCC). 79 pts (54.5%) were treated by anti PD-1 and 66 (45.5%) by anti PDL-1 agents. Overall as “best response”, 79 pts (54.5%) achieved DC (1 CR, 26 PR, 52 SD) and 66 pts (45.5%) had progressive disease (PD). DC was achieved in 41/79 (52%) pts treated by anti PD-1 and 38/66 (58%) pts treated by anti PDL-1: only 2/41 (5%) and 5/38 (13%) of them had high LDH levels at baseline, respectively. Among 107 pts in Group A, 72 (67.3%) achieved DC as compared to 7/38 pts (18.4%) with high levels of LDH (Group B-D) (p: 0.0001). In the latter groups, PD occurred in 17/23 (74%), 5/6 (83%) and 9/9 (100%) patients in the B, C and D group respectively. CONCLUSIONS: According to this preliminary analysis high baseline LDH serum levels seems to predict a greater likelihood of obtaining worse clinical outcome in terms of response and PFS also in patients treated by anti PD-1 and anti PDL-1 mAbs. In order to confirm this interesting result, we are evaluating a greater number of patients treated with anti PD-1 and anti PDL-1 mAbs at our Institution. Citation Format: Maria Silvia Cona, Valter Torri, Massimo Di Nicola, Marina Garassino, Michele Del Vecchio, Sara Cresta, Diego Signorelli, Silvia Damian, Matteo Duca, Alice Indini, Monica Niger, Filippo de Braud. Baseline LDH serum level as predictive value of activity in patients treated with anti PD-1 and PDL-1 monoclonal antibodies. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3943.

Identification and Characterization of MEDI4736, an Antagonistic Anti–PD-L1 Monoclonal Antibody

Programmed cell-death 1 ligand 1 (PD-L1) is a member of the B7/CD28 family of proteins that control T-cell activation. Many tumors can upregulate expression of PD-L1, inhibiting antitumor T-cell responses and avoiding immune surveillance and elimination. We have identified and characterized MEDI4736, a human IgG1 monoclonal antibody that binds with high affinity and specificity to PD-L1 and is uniquely engineered to prevent antibody-dependent cell-mediated cytotoxicity. In vitro assays demonstrate that MEDI4736 is a potent antagonist of PD-L1 function, blocking interaction with PD-1 and CD80 to overcome inhibition of primary human T-cell activation. In vivo MEDI4736 significantly inhibits the growth of human tumors in a novel xenograft model containing coimplanted human T cells. This activity is entirely dependent on the presence of transplanted T cells, supporting the immunological mechanism of action for MEDI4736. To further determine the utility of PD-L1 blockade, an anti-mouse PD-L1 antibody was investigated in immunocompetent mice. Here, anti-mouse PD-L1 significantly improved survival of mice implanted with CT26 colorectal cancer cells. The antitumor activity of anti-PD-L1 was enhanced by combination with oxaliplatin, which resulted in increased release of HMGB1 within CT26 tumors. Taken together, our results demonstrate that inhibition of PD-L1 function can have potent antitumor activity when used as monotherapy or in combination in preclinical models, and suggest it may be a promising therapeutic approach for the treatment of cancer. MEDI4736 is currently in several clinical trials both alone and in combination with other agents, including anti-CTLA-4, anti-PD-1, and inhibitors of IDO, MEK, BRAF, and EGFR.

Roles of the programmed cell death 1, T cell immunoglobulin mucin-3, and cluster of differentiation 288 pathways in the low reactivity of invariant natural killer T cells after chronic hepatitis B virus infection.

One of the main responses of invariant natural killer T (iNKT) cells to antigen stimulation is the rapid production of interleukin (IL)-4 and interferon (IFN)-γ cytokines. There is a decline in the function of iNKT cells in chronic hepatitis B (CHB) patients. In this study, we explored the impact of programmed cell death 1 (PD-1), T cell immunoglobulin mucin-3 (Tim-3), and cluster of differentiation 28 (CD28) expression on iNKT cell functions in CHB patients. Flow cytometry was used to test iNKT frequencies and levels of PD-1, Tim-3, CD28, IL-4, and IFN-γ secreted by iNKT cells. An enzyme-linked immunosorbent assay (ELISA) was used to measure IL-4 and IFN-γ secretion upon α-galactosylceramide (α-GalCer) activation ex vivo. We found that the levels of expression of PD-1 and Tim-3 from iNKT cells in CHB patients were significantly higher than in healthy donors (p<0.05), but there was lower expression of CD28 (p<0.05) and an impaired capability to produce IL-4 and IFN-γ (p<0.05). In vitro α-GalCer stimulation upregulated the expression of PD-1(+) iNKT cells (p<0.05), Tim-3(+) iNKT cells (p<0.05), and CD28(+) iNKT cells (p<0.05). In response to combination therapies consisting of α-GalCer and anti-PDL1 monoclonal antibody (mAb) and/or anti-Tim-3 mAbs and/or anti-CD80/anti-CD28 mAbs, IL-4(+) and IFN-γ(+) iNKT cells demonstrated different degrees of growth (p<0.05). The functional decline of iNKT cells was closely related to the decrease in CD28 expression and the increases of Tim-3 and PD-1. In addition, clinical antiviral treatment with lamivudine could partially restore the immune function of iNKT cells in CHB patients.

Pharmacokinetics of MEDI4736, a fully human anti-PDL1 monoclonal antibody, in patients with advanced solid tumors.

2602 Background: MEDI4736 is a human immunoglobulin G1 kappa (IgG1κ) monoclonal antibody directed against human programmed death ligand 1 (PD-L1). MEDI4736 blocks inhibitory interaction of PD-L1 wi...

Abstract PL07-02: The Renaissance of immunotherapy.

Abstract Bringing down the walls of defense The recent results of clinical trials with various anti-PD-1/PDL-1 monoclonal antibodies have converted many non-believers into believers of the enormous potential of immunomodulatory agents to gain control over some, if not many, solid tumors. Tackling immune suppression, seems to be a much more powerful intervention than short-lived immune-activating strategies and the current axioma of "inhibiting the inhibitor" and "breaking tolerance" appears to be a particularly powerful approach. This was first demonstrated by the success of anti-CTLA4 molecules which “prevent the downregulation of CTL activity and/or reawaken immuneresponses that have gone silent.” The focus these days is very much on anti-PD1 and anti-PDL1 monoclonal antibodies that can prevent the downregulation of CTL activity at the tumor site because of PDL1 expression on tumor cells. Taking down very effective walls of defense is essential to give immune-therapeutic strategies a chance. Immune-stimulation alone with T-cell agonists or cytokines or vaccines is rather ineffective when defense mechnisms are intact centrally (lymph nodes: mostly CTLA4) and peripherally (tumor site: mostly PDL1). Moreover anti-CTLA4 and anti-PD1/PDL1 can synergize in boosting an effective immuneresponse leading to long lasting responses in high percentages of patients. The concept of a clinical cure emerges, as chronic control of metastatic disease is an emerging reality in melanoma, with immuno-combos. It is clear that checkpoint inhibitors open the door for the effective use of agonists, such as OX40, 4BB-1 and CD137 and for synergy with cytokines such as IL2 and IFN. Key role of the immune system in various combination approaches The immune system is the key-component of long term responses, not only in immunotherapeutic approaches. There is an increasing body of evidence that patients with long term responses or “clinical cure” conditions after chemotherapy or targeted-agent therapies depend on immunogenic cell death mechanisms, (re)activation of the immune system and the presence of prominent immune-infiltrates in residual tumor lesions. Chemotherapeutics and targeted agents can lead to immunogenic or immune-tolerizing cell death, the first being associated with prolonged responses and control or even cure, the latter being associated with failure and death. Examples for immunogenic chemotherapeutics are anthracyclines, oxaliplatine, ionizing radiation and cyclophosphamide, whereas other chemotherapeutics (cisplatinum, mitomycin C, etoposide) have been found to induce unresponsiveness. Therapeutics that cause immunogenic cell death The molecular cues underlying this immunogenic cell death have been partly unveiled. Cell demise should be accompanied by an ER stress response which promotes calreticuline exposure and phagocytosis of dead cells by phagocytes. Next, autophagy is mandatory for ATP release and inflammatory monocytes to become dendritic cells (DC) priming T cell responses. Finally, HMGB1 release from the nucleus is indispensable to engage TLR4 on DC to accelerate the processing and antigen presentation to T lymphocytes By eliciting anticancer effector and memory T cells, immunogenic cell death contributes to the success of chemotherapy.Immunological off target effects have also been described for targeted agents and radiation therapy. Conclusions Clinical cures and eventually possibly a complete cancer cure becomes possible if we respect one basic principle: successful therapies require the induction / re-induction of anticancer immune responses. Renaissance is here. Citation Information: Mol Cancer Ther 2013;12(11 Suppl):PL07-02. Citation Format: Alexander M. Marie Eggermont. The Renaissance of immunotherapy. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr PL07-02.

B7h (ICOS-L) Maintains Tolerance at the Fetomaternal Interface

In a successful pregnancy, the semiallogeneic fetus is not rejected by the maternal immune system, which implies tolerance mechanisms protecting fetal tissues from maternal immune attack. Here we report that the ICOS-B7h costimulatory pathway plays a critical role in maintaining the equilibrium at the fetomaternal interface. Blockade of this pathway increased fetal resorption and decreased fetal survival in an allogeneic pregnancy model (CBA female × B6 male). Locally in the placenta, levels of regulatory markers such as IDO and TGF-β1 were reduced after anti-B7h monoclonal antibody treatment, whereas levels of effector cytokines (eg, IFN-γ) were significantly increased. In secondary lymphoid organs, enhanced IFN-γ and granzyme B production (predominantly by CD8(+) T cells) was observed in the anti-B7h-treated group. The deleterious effect of B7h blockade in pregnancy was maintained only in CD4 knockout mice, not in CD8 knockout mice, which suggests a role for CD8(+) Tcells in immune regulation by the ICOS-B7h pathway. In accord, regulatory CD8(+) T cells (in particular, CD8(+)CD103(+) cells) were significantly decreased after anti-B7h monoclonal antibody treatment, and adoptive transfer of this subset abrogated the deleterious effect of B7h blockade in fetomaternal tolerance. Taken together, these data support the hypothesis that B7h blockade abrogates tolerance at the fetomaternal interface by enhancing CD8(+) effector response and reducing local immunomodulation mediated by CD8(+) regulatory T cells.

PD‐1/PDL1 and CD28/CD80 pathways modulate natural killer T cell function to inhibit hepatitis B virus replication

α-Galactosylceramide (α-GalCer)-activated natural killer T (NKT) cells have antiviral properties against hepatitis B virus (HBV). However, α-GalCer activation of NKT cells can induce anergy. We hypothesized that this effect may be overcome by a treatment strategy that includes manipulation of CD28/CD80 costimulatory and PD-1/PDL1 coinhibitory signals of NKT cells, thereby enhancing the anti-HBV effect of α-GalCer. We established a transgenic mouse model of chronic HBV infection and investigated hepatic NKT cell frequencies, functions and expression of immunomodulatory factors. Our results showed that compared with uninfected control mice, hepatic NKT cells from HBV transgenic mice displayed lower frequencies (7.91% vs 16.74%, P<0.05), impaired capabilities to produce interferon (IFN)-γ (5.6% vs 1.4%, P<0.05) and interleukin (IL)-4 (6.8% vs 0.3%, P<0.05), higher expression of PD-1 (9.64% vs 6.36%, P<0.05) and lower expression of CD28 (5.05% vs 28.88%, P<0.05). However, when hepatic mononuclear cells (MNCs) were isolated from HBV transgenic mice, α-GalCer exposure in culture remarkably upregulated both PD-1(+) NKT cells (P<0.05) and CD28(+) NKT cells (P<0.05). Furthermore, when HBV transgenic mice were treated with combination therapies consisting of α-GalCer and anti-PDL1 monoclonal antibody (mAb) and/or anti-CD80/anti-CD28 mAbs, IFN-γ(+) NKT cell frequency was selectively increased (P<0.05) and HBV replication was suppressed; these effects were accompanied by varying degrees and types of liver damage. Surprisingly, activating CD28/CD80 signal in HBV transgenic mice was more effective but caused less liver injury than blocking PD-1/PDL1 signal in modulating αGalCer-activated NKT cell function to inhibit HBV infection. Our findings also show that combined therapy with blocking PD-1/PDL1 and activating CD28/CD80 signal in the presence of aGalCer cannot superimpose the effect of antivirus. α-GalCer combination therapy that modulates the CD28/CD80 pathways of NKT cells may represent a promising approach to inhibit HBV replication in chronically infected patients.

Program death-1 signaling and regulatory T cells collaborate to resist the function of adoptively transferred cytotoxic T lymphocytes in advanced acute myeloid leukemia

AbstractTumor-induced immune defects can weaken host immune response and permit tumor cell growth. In a systemic model of murine acute myeloid leukemia (AML), tumor progression resulted in increased regulatory T cells (Treg) and elevation of program death-1 (PD-1) expression on CD8+ cytotoxic T cells (CTLs) at the tumor site. PD-1 knockout mice were more resistant to AML despite the presence of similar percentage of Tregs compared with wild type. In vitro, intact Treg suppression of CD8+ T-cell responses was dependent on PD-1 expression by T cells and Tregs and PD-L1 expression by antigen-presenting cells. In vivo, the function of adoptively transferred AML-reactive CTLs was reduced by AML-associated Tregs. Anti–PD-L1 monoclonal antibody treatment increased the proliferation and function of CTLs at tumor sites, reduced AML tumor burden, and resulted in long-term survivors. Treg depletion followed by PD-1/PD-L1 blockade showed superior efficacy for eradication of established AML. These data demonstrated that interaction between PD-1 and PD-L1 can facilitate Treg-induced suppression of T-effector cells and dampen the antitumor immune response. PD-1/PD-L1 blockade coupled with Treg depletion represents an important new approach that can be readily translated into the clinic to improve the therapeutic efficacy of adoptive AML-reactive CTLs in advanced AML disease.

Abstract 5309: Programmed Death Ligand-1 expression on the cell surface is regulated by Costimulatory Molecule CD80 expressed by cancer vaccines

Abstract With the lack of effective treatments for metastatic cancers, the employment of immunotherapies, cell-based vaccines particularly, to activate a patient's own immune system is a promising approach for the treatment of disseminated metastatic cancer. Many tumor cells constitutively express or are induced by Interferonγ (IFNγ) to express the inhibitory molecule Programmed Death Ligand 1 (PDL1). Since many cell-based vaccines are derived from tumor cells, the expression of PDL1 could reduce the therapeutic efficacy of the vaccines. PDL1 binds to its receptor Programmed Death 1 (PD1) on T cells and can signal for either apoptosis of T cells or can prevent their activation. As determined by flow cytometry using three anti-PDL1 monoclonal antibodies (mAb) that detect distinct PDL1 epitopes, and human lung, uveal melanoma, cutaneous melanoma, and breast cancer cells, the over-expression of CD80 blocks constitutive and IFNγ-induced cell surface expression of PDL1. Quantitative analysis of CD80 and PDL1 expression indicates an inverse relationship between PDL1 and CD80. CD80+ tumor cells contain intracellular PDL1, as assessed by flow cytometry, suggesting that CD80 regulates PDL1 at the protein level. Tumor cells transfected with CD80 constructs lacking a cytoplasmic domain or with an irrelevant non-signaling cytoplasmic domain, retain the ability to block PDL1 expression at the cell surface indicating that CD80 does not modulate PDL1 transcription via intracellular signaling. These results suggest that in addition to serving as a costimulatory molecule, CD80 facilitates T cell activation by blocking coinhibitory signals and preventing T cell apoptosis. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 5309.

Programmed Death Ligand-1 expression on the cell surface is regulated by costimulatory molecule CD80 expressed by cancer vaccines (101.4)

Abstract Programmed Death Ligand 1 (PDL1) is a major obstacle in the development of cancer immunotherapies. PDL1 is constitutively expressed or induced by IFNγ on many tumor cells, resulting in the prevention of T cell activation or the apoptotic cell death of activated T cells. Cell-based vaccines previously developed in our lab were made by modifying tumor cells to express Major Histocompatibility Complex Class II (MHCII) and costimulatory B7-1 (CD80) molecules. These cell-based vaccines do not express PDL1, even after IFNγ stimulation. As determined by flow cytometry using three anti-PDL1 monoclonal antibodies that detect distinct PDL1 epitopes, and human lung, uveal and cutaneous melanoma, and breast cancer cells, the over-expression of CD80 blocks constitutive and IFNγ-induced cell surface expression of PDL1. Quantitative analysis of CD80 and PDL1 expression indicates an inverse relationship between PDL1 and CD80. CD80+ tumor cells contain intracellular PDL1, as assessed by flow cytometry, suggesting that CD80 regulates PDL1 at the protein level. Tumor cells transfected with CD80 constructs lacking a cytoplasmic domain or with an irrelevant non-signaling cytoplasmic domain, retain the ability to block PDL1 expression at the cell surface indicating that CD80 does not modulate PDL1 transcription. These results suggest that in addition to serving as a costimulatory molecule, CD80 facilitates T cell activation by blocking coinhibitory signals and preventing T cell apoptosis.

Clinical Significance and Therapeutic Potential of the Programmed Death-1 Ligand/Programmed Death-1 Pathway in Human Pancreatic Cancer

The programmed death-1 ligand/programmed death-1 (PD-L/PD-1) pathway has been recently suggested to play a pivotal role in the immune evasion of tumors from host immune system. In this study, we tried to reveal the clinical importance and therapeutic potential of the PD-L/PD-1 pathway in pancreatic cancer, which is one of the most aggressive and intractable malignant tumors. We used immunohistochemistry to investigate PD-L expression in 51 patients with pancreatic cancer who underwent surgery and explored the therapeutic efficacy of blocking the PD-L1/PD-1 pathway in murine pancreatic cancer in vivo. PD-L1-positive patients had a significantly poorer prognosis than the PD-L1-negative patients, whereas there was no significant correlation of tumor PD-L2 expression with patient survival. PD-L1 expression was inversely correlated with tumor-infiltrating T lymphocytes, particularly CD8(+) T cells. These clinical data have suggested that the PD-L1/PD-1 pathway may be a critical regulator in human pancreatic cancer. Monoclonal antibodies against PD-L1 or PD-1 induced a substantial antitumor effect on murine pancreatic cancer in vivo. PD-L1 blockade promoted CD8(+) T-cell infiltration into the tumor and induced local immune activation. Furthermore, the combination of anti-PD-L1 monoclonal antibody and gemcitabine exhibited a significant synergistic effect on murine pancreatic cancer and resulted in complete response without overt toxicity. Our data suggest for the first time that PD-L1 status may be a new predictor of prognosis for patients with pancreatic cancer and provide the rationale for developing a novel therapy of targeting the PD-L/PD-1 pathway against this fatal disease.