anti-PDL1 mAb Research Articles

A phase III trial to compare atezolizumab (atezo) vs best supportive care (BSC) following adjuvant chemotherapy in patients (pts) with completely resected NSCLC: IMpower010.

TPS8576 Background: The anti–PD-L1 mAb atezo blocks the interaction between PD-L1 and its receptors PD-1 and B7.1 and restores anti-tumor immunity. In the OAK trial, pts with 2L/3L advanced NSCLC had improved mOS in the atezo arm (13.8 mo) vs the docetaxel (doc) arm (9.6 mo), with a survival benefit observed regardless of PD-L1 expression levels on tumor cells (TC) or tumor-infiltrating immune cells (IC). However, more effective treatment options are needed for pts with early-stage NSCLC. A global Phase III, randomized, open-label trial, IMpower010 (NCT02486718), is being conducted to evaluate the efficacy and safety of atezo vs BSC following adjuvant cisplatin (cis)–based chemotherapy (chemo) in pts with resected stage IB (tumors ≥ 4 cm)-IIIA NSCLC. Methods: Pts eligible for study must have complete tumor resection 4 to 12 weeks prior to enrollment for pathologic stage IB (tumors ≥ 4 cm)-IIIA NSCLC, be adequately recovered from surgery, be able to receive cis-based adjuvant chemo and have an ECOG PS 0-1. Pts with other malignancies, autoimmune disease, hormonal cancer or radiation therapy within 5 years and prior chemo or immunotherapy are excluded from study. Approximately 1127 pts will be enrolled regardless of PD-L1 status. Pts will receive up to four 21-d cycles of cis-based chemo (cis [75 mg/m2 IV, d 1] + vinorelbine [30 mg/m2 IV, d 1, 8], doc [75 mg/m2 IV, d 1] or gemcitabine [1250 mg/m2 IV, d 1, 8], or pemetrexed [500 mg/m2 IV, d 1; only non-squamous NSCLC]). No adjuvant radiation therapy is permitted. After adjuvant chemo, eligible pts will be randomized 1:1 to receive 16 cycles of atezo 1200 mg q3w or BSC. Stratification factors include sex, histology (squamous vs non-squamous), disease stage (IB vs II vs IIA) and PD-L1 status by IHC (TC2/3 [≥ 5% expressing PD-L1] and any IC vs TC0/1 [ < 5%] and IC2/3 vs TC0/1 and IC0/1 [ < 5%]). The primary endpoint is disease-free survival; secondary endpoints include OS and safety. Exploratory biomarkers, including PD-L1 expression, immune- and tumor-related biomarkers before, during and after treatment with atezo and at radiographic disease recurrence, or confirmation of new primary NSCLC, will be evaluated. Clinical trial information: NCT02486718.

OA03.02 Atezolizumab as 1L Therapy for Advanced NSCLC in PD-L1–Selected Patients: Updated ORR, PFS and OS Data from the BIRCH Study

Atezolizumab, a humanized anti-PDL1 mAb, inhibits the PD-L1/PD-1 pathway to restore tumor-specific T-cell immunity, resulting in durable anti-tumor effects. BIRCH (NCT02031458) is a single-arm Phase II study of atezolizumab monotherapy in PD-L1–selected advanced NSCLC patients, across multiple therapy lines. Primary analyses (median follow-up, 8.5 months) demonstrated a meaningful ORR with durable response in chemotherapy-naive 1L and 2L+ PD-L1–selected patients. Here we report updated efficacy data in 1L patients. 1L eligibility criteria included PD-L1–selected, advanced-stage NSCLC with no CNS metastases or prior chemotherapy. PD-L1 was centrally evaluated (VENTANA SP142 IHC assay). Patients expressing PD-L1 on ≥5% of tumor cells (TC) or tumor-infiltrating immune cells (IC), ie, TC2/3 or IC2/3, were enrolled. Patients with EGFR mutation or ALK rearrangement must have had prior TKI treatment. Atezolizumab 1200mg was administered IV q3w until radiographic disease progression or unacceptable toxicity. The primary endpoint was independent review facility(IRF)-assessed ORR. Secondary endpoints included investigator(INV)-assessed ORR, DOR, PFS (RECIST v1.1) and OS. With a median follow-up of 14.6 months, median OS was not reached in TC3 or IC3 patients and was 20.1 months in TC2/3 or IC2/3 (ITT) patients; INV-assessed ORR was 32% and 24%, respectively (Table). Furthermore, ORR was 31% for mutant EGFR (n=13) vs 20% for wild-type EGFR patients (n=104), and 27% for mutant KRAS (n=33) vs 21% for wild-type KRAS patients (n=67). No new safety signals were observed. Updated efficacy (including IRF ORR), safety and exploratory biomarker analyses will be presented. With longer follow-up, atezolizumab continued to demonstrate promising efficacy in 1L NSCLC. These results indicate that atezolizumab has durable efficacy in the 1L setting, in EGFR and KRAS mutant and wild-type tumors, and support ongoing Phase III trials evaluating atezolizumab vs chemotherapy in 1L NSCLC.Tabled 1Endpoint (95% CI)TC3 or IC3a (n=65)TC2/3 or IC2/3b (n=139)INV ORR, %32% (21.2–45.1)24% (16.9–31.7)EGFR mutant/wild-type, %25%/29%31%/20%KRAS mutant/wild-type, %38%/27%27%/21%mDOR, mo13.1 (8.5–NE)13.1 (9.9–17.5)mOS, moNE (12.0–NE)20.1 (20.1–NE)12-mo OS rate, %61% (48.8–73.8)66% (57.9–74.5)mPFS, mo7.3 (4.9–12.0)7.3 (5.6–9.1)12-mo PFS rate, %36% (23.8–48.8)32% (24.0–40.7)NE, not estimable.a TC ≥50% or IC ≥10% PD-L1–expressing cells.b TC or IC ≥5% PD-L1–expressing cells. Open table in a new tab

P3.02c-042 IMpower110: Phase III Trial Comparing 1L Atezolizumab with Chemotherapy in PD-L1–Selected Chemotherapy-Naive NSCLC Patients: Topic: IT

For patients with advanced NSCLC without genetic driver alterations, cisplatin/carboplatin+pemetrexed is a standard-of-care first-line (1L) treatment for non-squamous histology; and cisplatin/carboplatin+gemcitabine for squamous histology. Although immunotherapies targeting PD-L1/PD-1 are currently available for 2L+ NSCLC, chemotherapy remains the main 1L option despite poor survival and toxicities. Atezolizumab, an anti–PDL1 mAb, prevents PD-L1 from interacting with its receptors PD-1 and B7.1, restoring tumor-specific T-cell immunity. Clinical efficacy was demonstrated with atezolizumab in non-squamous and squamous NSCLC, with Phase I and II studies exhibiting durable responses and survival benefit that increases with higher PD-L1 expression on tumor cells (TC) and/or tumor-infiltrating immune cells (IC). IMpower110, a global Phase III randomized, multicenter, open-label trial, will evaluate efficacy and safety of atezolizumab vs cisplatin/carboplatin+pemetrexed or gemcitabine as 1L therapy for PD-L1–selected chemotherapy-naive patients with advanced non-squamous or squamous NSCLC, respectively. Eligibility criteria include stage IV non-squamous or squamous NSCLC, measurable disease (RECIST v1.1), ECOG PS 0-1, no prior chemotherapy for advanced NSCLC and centrally-assessed PD-L1 expression ≥1% on TC or IC (TC1/2/3 or IC1/2/3 with VENTANA SP142 IHC assay; expected prevalence, ≈65%). Exclusion criteria include active or untreated CNS metastases, prior immune checkpoint blockade therapy or autoimmune disease. Patients will be randomized 1:1 to receive atezolizumab or cisplatin/carboplatin+pemetrexed (non-squamous)/gemcitabine (squamous) for 4 or 6 21-day cycles. Patients in comparator arms can receive pemetrexed (non-squamous)/best supportive care (squamous) until RECIST v1.1 disease progression. Patients receiving atezolizumab may continue until loss of clinical benefit. Co-primary endpoints are PFS and OS. Key secondary efficacy endpoints include ORR, DOR, IRF-assessed PFS (RECIST v1.1) and TTD. Safety and PK will also be evaluated. Tumor biopsies at RECIST v1.1 progression will be assessed for immunologic biomarkers associated with responses to atezolizumab and to differentiate non-conventional responses from radiographic progression.Tabled 1Planned enrollment, N570HistologyNon-squamousSquamousExperimental armAtezolizumab (1200 mg q3w)Comparator armCisplatin (75 mg/m2 IV q3w) + pemetrexed (500 mg/m2 IV q3w) or Carboplatin (AUC 6 mg/mL/min IV q3w) + pemetrexed (500 mg/m2 IV q3w)Cisplatin (75 mg/m2 IV q3w) + gemcitabine (1200 mg/m2 IV days 1, 8) or Carboplatin (AUC 5 mg/mL/min IV q3w) + gemcitabine (1000 mg/m2 IV days 1, 8)Stratification factors• Sex• ECOG• Histology (non-squamous vs squamous)• PD-L1 expression by IHCClinicalTrials.gov identifierNCT02409342 Open table in a new tab Section not applicable. Section not applicable.

Abstract PR12: Targeting FSTL1 augments therapeutic activities of immune checkpoint inhibitors

Abstract Purpose: Tumor heterogeneity is composed of genetic and phenotypic changes in tumor itself, and also of the consequence of reciprocal evolution together with the tumor microenvironment containing a variety of cells such as stromal cells, vascular cells and immune cells in the host. Imbalanced immunity is one of the major problems supporting tumor progression and then amplification of the heterogeneity. Many inhibitors specific for immune checkpoint molecules interfering induction of anti-tumor immunity have been recently developed in clinical settings, and the clinical responses have convinced us of its efficaciousness. However, good results are limited to a part of the treated patients, and additional but another strategy is needed for treating patients more efficiently and effectively. For the purpose, we have been investigating the complex network in the tumor milieu and the systemic responses in the whole body comprehensively and collectively, and previously identified a BMP family FSTL1, which is significantly secreted from Snail+ cancer stem-like cells, as a key effector molecule in the cancer-associated immune suppression and dysfunction. FSTL1 expands pluripotent mesenchymal stem/stromal cells (MSCs), which generate immunoregulatory cells such as Tregs and tolerogenic DCs, and functionally impaired CD8-low T cells. FSTL1 and its induced MSCs also confer higher invasive and metastatic properties on tumor cells leading to further promotion of tumor growth and metastasis. To prevent such FSTL1-caused vicious circulation, we established anti-FSTL1 blocking mAbs, and evaluated the anti-tumor efficacy in combination with immune checkpoint inhibitors (ICIs) using mouse FSTL1+ tumor models. Experimental Procedures: We generated monoclonal antibodies (mAbs) specific for both mouse and human FSTL1 utilizing the chicken immunization system followed by constructing cDNA phage library. After in vitro screening, the established anti-FSTL1 mAbs were tested for the in vivo anti-tumor activity using two syngeneic tumor models: a bone metastatic tumor model that C57BL/6 was implanted with snail-transduced melanoma B16-F10 cells, and a lung metastatic tumor model that BALB/c was implanted with colon cancer intrinsic FSTL1+ CT26 cells. The mAbs (10mg/kg) were intraperitoneally injected into these mice twice on day 4 and day 7 after tumor implantation. On day 14, immunological analysis was conducted using tumor-infiltrating cells, spleen cells and bone marrow cells obtained from the mice. Results: We established chicken/mouse chimeric anti-FSTL1 mAb capable of inhibiting the FSTL1-elicited events including MSC expansion, immunoregulatory cell induction, and tumor invasion in vitro. In both bone and lung metastatic tumor models, treatment with the anti-FSTL1 mAb induced tumor-specific CD8+ T cells with higher CTL activities by suppressing increase of MSCs, but not Tregs and MDSCs, and significantly suppressed subcutaneous tumor growth and metastasis in the treated mice as compared to those of the control mice. The ICI mono-therapy was insufficient to suppress increase of MSCs, although significantly reduced immunoregulatory cells, and the anti-tumor efficacy was almost similar. Combination with the anti-FSTL1 mAb synergistically and significantly enhanced the ICI mono-therapeutic efficacy, particularly anti-PDL1 mAb, by inducing potent tumor-specific CTLs, resulting in tumor-free in some of the treated mice. Conclusions: Blocking FSTL1 reprograms and properly induces anti-tumor immunity by switching the tumor-supportive immune directivity to the active mode against cancer. Anti-FSTL1 mAb having totally different molecular mechanisms from the conventional ICIs may be a promising partner for radically correcting cancer-manipulated immunity in clinical settings. Citation Format: Chie Kudo-Saito, Yamato Ogiwara, Marina Hennmi, Kazunori Aoki. Targeting FSTL1 augments therapeutic activities of immune checkpoint inhibitors [abstract]. In: Proceedings of the Second CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; 2016 Sept 25-28; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2016;4(11 Suppl):Abstract nr PR12.

Antibody-Dependent Cellular Cytotoxicity Activity of a Novel Anti-PD-L1 Antibody Avelumab (MSB0010718C) on Human Tumor Cells.

Several anti-PD-1/PD-L1 monoclonal antibodies (mAb) are currently providing evidence of clinical benefit in subsets of cancer patients. The mode of action of these mAbs is to inhibit PD-1 on immune cells interacting with PD-L1 on tumor cells. These mAbs are either designed or engineered to eliminate antibody-dependent cell-mediated cytotoxicity (ADCC), which, however, has been implicated as an important mechanism in several highly effective mAb-mediated cancer therapies. A fully human anti-PD-L1 mAb would potentially be able to block PD-1/PD-L1 interactions and also mediate the ADCC lysis of tumor cells. MSB0010718C (designated avelumab) is a fully human IgG1 anti-PD-L1 mAb. The studies reported here demonstrate (i) the ability of avelumab to lyse a range of human tumor cells in the presence of PBMC or NK effectors; (ii) IFNγ can enhance tumor cell PD-L1 expression and, in some cases, enhance ADCC tumor cell lysis; (iii) purified NK cells are potent effectors for avelumab; (iv) similar levels of avelumab-mediated ADCC lysis of tumor cells are seen using purified NK as effectors from either healthy donors or cancer patients; (v) very low levels of avelumab-mediated lysis are seen using whole PBMCs as targets; this finding complements results seen in analyses of PBMC subsets of patients receiving avelumab; and (vi) the addition of IL12 to NK cells greatly enhances avelumab-mediated ADCC. These studies thus provide an additional mode of action for an anti-PD-L1 mAb and support the rationale for further studies to enhance avelumab-mediated ADCC activity.

Abstract 250: Differential efficacy of immune checkpoint inhibitors on bone metastasis and its associated immune dysfunction

Abstract Purposes: We previously demonstrated that Snail expression in tumor cells promotes bone metastasis not only by enhancing motility and bone polarity of tumor cells, but also by hindering anti-tumor immunity via increase of immunoregulatory cells including CD4(+)Foxp3(+) Tregs, CD11c(+)MHC II(-/low)PDL1(+) DCregs and CD45(-)ALCAM(+) mesenchymal stem cells (MSCs), and the consequent CD8(low)Tim3(+)PD1(+) exhausted/impaired T cells. In this study, we examined whether immune checkpoint inhibitors targeting CTLA4, PD1 or PDL1 would rescue from the bone metastasis-associated immune dysfunction using a bone metastasis tumor model that we previously established. Results: C57BL/6 mice are implanted with snail-transduced B16-F10 melanoma cells both subcutaneously and intravenously, and were intraperitoneally injected with anti-CTLA4, anti-PD1, or anti-PDL1 mAb, or the isotype IgG as a control (10 mg/kg) on days 5 and 8 after tumor implantation. Treatment with any immune checkpoint inhibitors significantly inhibited increase of CD4(+)Foxp3(+) Tregs followed by increase of tumor-specific CD8(+) T cells in the subcutaneous tumors, resulting in significant suppression of the tumor growth as compared to that of the control group. Unexpectedly, however, bone metastasis was rather promoted in these treated mice. Nevertheless, anti-PDL1-treated mice survived in good condition for a long time, although anti-CTLA4 or anti-PD1-treated emaciated mice died earlier than the control mice. In the mice receiving anti-CTLA4 or anti-PD1 mAb, although CD4(+)Foxp3(+) Tregs systemically decreased, other immunoregulatory cells such as CD45(-)ALCAM(+) MSCs, CD11b(+)Gr1(+) MDSCs and CD8(+)Foxp3(+) Tregs, and impaired CD8(low)Tim3(+)PD1(+) T cells systemically increased more than those in the control group. In addition, tumor cells isolated from the bone marrow (BM) formed a lot of larger sphere colonies in the matrigel culture than those of the control group, and were resistant to chemotherapeutics and CTLs, indicating cancer stem-like features. In contrast, in the anti-PDL1-treated mice, tumor-specific CD8(+) T cells were systemically induced, although immunoregulatory or impaired cells still increased. Interestingly, the BM-isolated tumor cells were quite different from those of other groups: high adhesive and chemo/CTL-sensitive, suggesting tumor transition into a less malignant epithelial type. The molecular mechanisms underlying these effects are now being investigated in detail. Conclusions: These results suggest that anti-PDL1 mAb is effective in treating bone metastasis by modulating both host immunity and tumor cells. Our study, at least using this tumor model, also gives a caution in the application of anti-CTLA4 and anti-PD1 mAb for cancer patients with bone metastasis. Citation Format: Chie Kudo-Saito, Takafumi Fuwa, Kouichi Murakami. Differential efficacy of immune checkpoint inhibitors on bone metastasis and its associated immune dysfunction. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 250. doi:10.1158/1538-7445.AM2015-250

Combinatorial Immunotherapy of Polyinosinic–Polycytidylic Acid and Blockade of Programmed Death-Ligand 1 Induce Effective CD8 T-cell Responses against Established Tumors

Epitope-based cancer vaccines capable of inducing CD8 T-cell responses to tumor-associated antigens (TAA) expressed by tumor cells have been considered as attractive alternatives for the treatment of some types of cancer. However, reliable TAAs have not been identified for most malignant diseases, limiting the development of epitope-based vaccines. Herein, we report that the combinatorial therapy of polyinosinic-polycytidylic acid (poly-IC) and antiprogrammed death-ligand 1 (PD-L1) monoclonal antibody (mAb) can be implemented with good results for tumors where no known TAAs have been identified. Three cancer mouse models (melanoma, lung, and colon) were used to evaluate therapeutic efficacy and examine the immunologic mechanisms of the poly-IC/anti-PD-L1 mAb therapy. The combined administration of poly-IC and anti-PD-L1 mAb into tumor-bearing mice generated potent immune responses resulting in the complete eradication or remarkable reduction of tumor growth. In some instances, the poly-IC/anti-PD-L1 mAb therapy induced long-lasting protection against tumor rechallenges. The results indicate that CD8 T cells but not CD4 T cells or NK cells mediated the therapeutic efficacy of this combinatorial therapy. Experiments using genetically deficient mice indicate that the therapeutic efficacy of this combinatorial therapy depended in part by the participation of type-I IFN, whereas IFN-γ did not seem to play a major role. The overall results suggest that immunotherapy consisting of the combination of poly-IC/anti-PD-L1 mAb could be a promising new approach for treating patients with cancer, especially those instances where no reliable TAAs are available as a therapeutic vaccine.

The Programmed Death-1 Ligand 1:B7-1 Pathway Restrains Diabetogenic Effector T Cells In Vivo

Programmed death-1 ligand 1 (PD-L1) is a coinhibitory molecule that negatively regulates multiple tolerance checkpoints. In the NOD mouse model, PD-L1 regulates the development of diabetes. PD-L1 has two binding partners, programmed death-1 and B7-1, but the significance of the PD-L1:B7-1 interaction in regulating self-reactive T cell responses is not yet clear. To investigate this issue in NOD mice, we have compared the effects of two anti-PD-L1 Abs that have different blocking activities. Anti-PD-L1 mAb 10F.2H11 sterically and functionally blocks only PD-L1:B7-1 interactions, whereas anti-PD-L1 mAb 10F.9G2 blocks both PD-L1:B7-1 and PD-L1:programmed death-1 interactions. Both Abs had potent, yet distinct effects in accelerating diabetes in NOD mice: the single-blocker 10F.2H11 mAb was more effective at precipitating diabetes in older (13-wk-old) than in younger (6- to 7-wk-old) mice, whereas the dual-blocker 10F.9G2 mAb rapidly induced diabetes in NOD mice of both ages. Similarly, 10F.2H11 accelerated diabetes in recipients of T cells from diabetic, but not prediabetic mice, whereas 10F.9G2 was effective in both settings. Both anti-PD-L1 mAbs precipitated diabetes in adoptive transfer models of CD4(+) and CD8(+) T cell-driven diabetes. Taken together, these data demonstrate that the PD-L1:B7-1 pathway inhibits potentially pathogenic self-reactive effector CD4(+) and CD8(+) T cell responses in vivo, and suggest that the immunoinhibitory functions of this pathway may be particularly important during the later phases of diabetogenesis.

The Novel Costimulatory Programmed Death Ligand 1/B7.1 Pathway Is Functional in Inhibiting Alloimmune Responses In Vivo

The programmed death ligand 1 (PDL1)/programmed death 1 (PD1) costimulatory pathway plays an important role in the inhibition of alloimmune responses as well as in the induction and maintenance of peripheral tolerance. It has been demonstrated recently that PDL1 also can bind B7.1 to inhibit T cell responses in vitro. Using the bm12 into B6 heart transplant model, we investigated the functional significance of this interaction in alloimmune responses in vivo. PD1 blockade unlike PDL1 blockade failed to accelerate bm12 allograft rejection, suggesting a role for an additional binding partner for PDL1 other than PD1 in transplant rejection. PDL1 blockade was able to accelerate allograft rejection in B7.2-deficient recipients but not B7.1-deficient recipients, indicating that PDL1 interaction with B7.1 was important in inhibiting rejection. Administration of the novel 2H11 anti-PDL1 mAb, which only blocks the PDL1-B7.1 interaction, aggravated chronic injury of bm12 allografts in B6 recipients. Aggravated chronic injury was associated with an increased frequency of alloreactive IFN-γ-, IL-4-, and IL-6-producing splenocytes and a decreased percentage of regulatory T cells in the recipients. Using an in vitro cell culture assay, blockade of the interaction of PDL1 on dendritic cells with B7.1 on T cells increased IFN-γ production from alloreactive CD4(+) T cells, whereas blockade of dendritic cell B7.1 interaction with T cell PDL1 did not. These data indicate that PDL1 interaction with B7.1 plays an important role in the inhibition of alloimmune responses in vivo and suggests a dominant direction for PDL1 and B7.1 interaction.

Differential effects of blocking PD-1/PDL1 interaction in enhancing virus specific CD8 T cell response in young and aged mice (67.4)

Abstract In this report, we compared the impact of blocking PD-1/PDL1 interaction to the virus specific CD8 T cell function in young and old C57BL/6 mice. Anti-PDL1 mAb treatment at the time of foot-pad HSV-1 infection to young C57BL/6 mice resulted in significantly increased proportion of SSIEFARL specific effector CD8 T cells in popliteal lymph node (PLN), spleen and PBMC. The frequency of IFN-γ, TNF-α and IL2, secreting SSIEFARL specific CD8 T cells was also increased in anti-PDL1 treated mice in comparison to isotype treated groups. An increased proportion of granzyme B expressing CD8 T cells were determined in PLN and spleen of anti-PDL1 treated mice. Interestingly, blocking of PD-1/PDL1 interaction at the time of CD8 T cell priming in young mice also improved the quality of HSV-1 specific memory CD8 T cell pool as noted by an enhanced recall response to SSIEFARL encoding vaccinia virus. On the contrary, blocking PD-1/PDL-1 interaction in aged mice increased SSIEFARL specific CD8 T cells only in PLN but not in spleen and PBMC. Moreover, frequency of effector molecules (IFN-γ, TNF-α, IL-2 and Granzyme B) expressing CD8 T cells did not change significantly in any of the collected tissues. Additionally, unlike in young mice, α-PDL1 treatment during priming failed to improve the quality of memory CD8 T cell response in aged mice. Taken together, we suggest that blocking of PD-1/PDL-1 interaction during priming enhance HSV-1 specific CD8 T cell response in young but not in aged mice.

Anti-Programmed Cell Death 1 Antibody Reduces CD4+PD-1+ T Cells and Relieves the Lupus-Like Nephritis of NZB/W F1 Mice

Programmed cell death 1 (PD-1) is an immunosuppressive receptor that transduces an inhibitory signal into activated T cells. Although a single nucleotide polymorphism in the gene for PD-1 is associated with susceptibility to systemic lupus erythematosus, the role of PD-1 in systemic lupus erythematosus is still not well understood. In this study, we used NZB/W F1 mice, a model of lupus-like nephritis, to examine the function of PD-1 and its ligands. PD-1 was predominantly expressed on CD4(+) T cells that infiltrated the kidney, and CD4(+)PD-1(high) T cells produced higher levels of IFN-gamma than CD4(+)PD-1(low) or CD4(+)PD-1(-) T cells. Stimulation with PMA/ionomycin caused splenic CD4(+)PD-1(+) T cells to secrete high levels of IFN-gamma, IL-10, low levels of TNF-alpha, faint levels of IL-2, IL-21, and no IL-4, IL-17. In vivo anti-PD-1 mAb treatment reduced the number of CD4(+)PD-1(+) T cells in the kidney of NZB/W F1 mice and significantly reduced their mortality rate (p = 0.03). Conversely, blocking PD-L1 using an anti-PD-L1 mAb increased the number of CD4(+)PD-1(+) T cells in the kidney, enhanced serum IFN-gamma, IL-10, and IgG2a ds-DNA-Ab levels, accelerated the nephritis, and increased the mortality rate. We conclude that CD4(+)PD-1(high) T cells are dysregulated IFN-gamma-producing, proinflammatory cells in NZB/W F1 mice.