Janis M Taube

Johns Hopkins University, Baltimore, Maryland, United States

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Publications (85)526.9 Total impact

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    ABSTRACT: Objective: Recent data supports a significant role for immune checkpoint inhibitors in the treatment of solid tumours. Here, we evaluate gastric and gastro-oesophageal junction (G/GEJ) adenocarcinomas for their expression of programmed death-ligand 1 (PD-L1), infiltration by CD8+ T cells and the relationship of both factors to patient survival. Design: Thirty-four resections of primary invasive G/GEJ were stained by immunohistochemistry for PD-L1 and CD8 and by DNA in situ hybridisation for Epstein-Barr virus (EBV). CD8+ T cell densities both within tumours and at the tumour-stromal interface were analysed using whole slide digital imaging. Patient survival was evaluated according to PD-L1 status and CD8 density. Results: 12% of resections showed tumour cell membranous PD-L1 expression and 44% showed expression within the immune stroma. Two cases (6%) were EBV positive, with one showing membranous PD-L1 positivity. Increasing CD8+ densities both within tumours and immune stroma was associated with increasing percentage of tumour (p=0.027) and stromal (p=0.005) PD-L1 expression. Both tumour and immune stromal PD-L1 expression and high intratumoral or stromal CD8+ T cell density (>500/mm(2)) were associated with worse progression-free survival (PFS) and overall survival (OS). Conclusions: PD-L1 is expressed on both tumour cells and in the immune stroma across all stages and histologies of G/GEJ. Surprisingly, we demonstrate that increasing CD8 infiltration is correlated with impaired PFS and OS. Patients with higher CD8+ T cell densities also have higher PD-L1 expression, indicating an adaptive immune resistance mechanism may be occurring. Further characterisation of the G/GEJ immune microenvironment may highlight targets for immune-based therapy.
    No preview · Article · Jan 2016 · Gut
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    ABSTRACT: Alterations in EGFR, KRAS, and ALK are oncogenic drivers in lung cancer, but how oncogenic signaling influences immunity in the tumor microenvironment is just beginning to be understood. Immunosuppression likely contributes to lung cancer, because drugs that inhibit immune checkpoints like PD-1 and PD-L1 have clinical benefit. Here, we show that activation of the AKT-mTOR pathway tightly regulates PD-L1 expression in vitro and in vivo. Both oncogenic and IFNγ-mediated induction of PD-L1 was dependent on mTOR. In human lung adenocarcinomas and squamous cell carcinomas, membranous expression of PD-L1 was significantly associated with mTOR activation. These data suggest that oncogenic activation of the AKT-mTOR pathway promotes immune escape by driving expression of PD-L1, which was confirmed in syngeneic and genetically engineered mouse models of lung cancer where an mTOR inhibitor combined with a PD-1 antibody decreased tumor growth, increased tumor-infiltrating T cells, and decreased regulatory T cells. Cancer Res; 76(2); 1-12. ©2015 AACR.
    No preview · Article · Dec 2015 · Cancer Research
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    ABSTRACT: The fourth "Melanoma Bridge Meeting" took place in Naples, December 3-6th, 2014. The four topics discussed at this meeting were: Molecular and Immunological Advances, Combination Therapies, News in Immunotherapy, and Tumor Microenvironment and Biomarkers. Until recently systemic therapy for metastatic melanoma patients was ineffective, but recent advances in tumor biology and immunology have led to the development of new targeted and immunotherapeutic agents that prolong progression-free survival (PFS) and overall survival (OS). New therapies, such as mitogen-activated protein kinase (MAPK) pathway inhibitors as well as other signaling pathway inhibitors, are being tested in patients with metastatic melanoma either as monotherapy or in combination, and all have yielded promising results. These include inhibitors of receptor tyrosine kinases (BRAF, MEK, and VEGFR), the phosphatidylinositol 3 kinase (PI3K) pathway [PI3K, AKT, mammalian target of rapamycin (mTOR)], activators of apoptotic pathway, and the cell cycle inhibitors (CDK4/6). Various locoregional interventions including radiotherapy and surgery are still valid approaches in treatment of advanced melanoma that can be integrated with novel therapies. Intrinsic, adaptive and acquired resistance occur with targeted therapy such as BRAF inhibitors, where most responses are short-lived. Given that the reactivation of the MAPK pathway through several distinct mechanisms is responsible for the majority of acquired resistance, it is logical to combine BRAF inhibitors with inhibitors of targets downstream in the MAPK pathway. For example, combination of BRAF/MEK inhibitors (e.g., dabrafenib/trametinib) have been demonstrated to improve survival compared to monotherapy. Application of novel technologies such sequencing have proven useful as a tool for identification of MAPK pathway-alternative resistance mechanism and designing other combinatorial therapies such as those between BRAF and AKT inhibitors. Improved survival rates have also been observed with immune-targeted therapy for patients with metastatic melanoma. Immune-modulating antibodies came to the forefront with anti-CTLA-4, programmed cell death-1 (PD-1) and PD-1 ligand 1 (PD-L1) pathway blocking antibodies that result in durable responses in a subset of melanoma patients. Agents targeting other immune inhibitory (e.g., Tim-3) or immune stimulating (e.g., CD137) receptors and other approaches such as adoptive cell transfer demonstrate clinical benefit in patients with melanoma as well. These agents are being studied in combination with targeted therapies in attempt to produce longer-term responses than those more typically seen with targeted therapy. Other combinations with cytotoxic chemotherapy and inhibitors of angiogenesis are changing the evolving landscape of therapeutic options and are being evaluated to prevent or delay resistance and to further improve survival rates for this patient population. This meeting's specific focus was on advances in combination of targeted therapy and immunotherapy. Both combination targeted therapy approaches and different immunotherapies were discussed. Similarly to the previous meetings, the importance of biomarkers for clinical application as markers for diagnosis, prognosis and prediction of treatment response was an integral part of the meeting. The overall emphasis on biomarkers supports novel concepts toward integrating biomarkers into contemporary clinical management of patients with melanoma across the entire spectrum of disease stage. Translation of the knowledge gained from the biology of tumor microenvironment across different tumors represents a bridge to impact on prognosis and response to therapy in melanoma.
    Full-text · Article · Nov 2015 · Journal of Translational Medicine
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    ABSTRACT: Programmed death ligand 1 (PD-L1) expression by tumor-infiltrating lymphocytes (TILs) and tumor cells in breast cancer has been reported, but the relationships between PD-L1 expression by TIL, carcinoma cells, and other immunologic features of the breast tumor microenvironment remain unclear. We therefore evaluated the interrelationships between tumor cell surface and TIL PD-L1 expression, lymphocyte subpopulations, and patterns of immune cell infiltration in cohorts of treatment-naive, primary breast cancers (PBCs) (n = 45) and matched PBC and metastatic breast cancers (MBC) (n = 26). Seventy-eight percent of untreated PBCs contained PD-L1(+) TILs, but only 21% had PD-L1(+) carcinoma cells. Carcinoma PD-L1 expression localized to the tumor invasive front and was associated with high tumor grade (P = .04). Eighty-nine percent of PD-L1(+) carcinomas contained brisk TIL infiltrates, compared to only 24% of PD-L1(-) carcinomas; this included CD3(+) (P = .02), CD4(+) (P = .04), CD8(+) (P = .002), and FoxP3(+) T cells (P = .02). PD-L1(+) PBCs were more likely to contain PD-L1(+) TIL than PD-L1(-) PBCs (P = .04). Peripheral lymphoid aggregates were present in 100% of PD-L1(+) compared to 41% of PD-L1(-) PBC (P < .001). No patient with PD-L1(+) PBC developed distant recurrence, compared to 15% of patients with PD-L1(-) PBC. For the matched PBC and MBC cohort, 2 patients (8%) had PD-L1(+) tumors, with 1 case concordant and 1 case discordant for carcinoma PD-L1 expression in the PBC and MBC. Our data support PD-L1 expression by tumor cells as a biomarker of active breast tumor immunity and programmed death 1 blockade as a therapeutic strategy for breast cancer.
    No preview · Article · Nov 2015 · Human pathology

  • No preview · Article · Nov 2015
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    ABSTRACT: BACKGROUND The shave biopsy using a razor with an open blade is the current standard of care for sampling superficial skin lesions.OBJECTIVE To enhance safety, the authors developed a novel biopsy device with a closed blade design for removing the epidermal layer of skin and evaluated against the open razor blade for tolerability, scarring, and accuracy in histological diagnosis.MATERIALS AND METHODS Shave biopsies were performed using the novel device or razor blade on benign epidermal skin lesions in 10 patients on comparable body parts. Digital photography, colorimetry, scar scale evaluations, and questionnaires were used to evaluate the efficacy and tolerability of the devices.RESULTSFor all patients, accurate histological diagnoses were made regardless of device type. No statistically significant differences were detected between the novel device and razor blade in terms of scar scale assessments, colorimetry, and questionnaire responses. Both patients and the participating dermatologist reported satisfaction with the safety and performance of the novel device. No injuries to the provider occurred with either instrument.CONCLUSION The rotating sphere biopsy device is a potential alternative to the razor blade with comparable tolerability, scarring, and accuracy in histological diagnoses, offering improved safety for patients and health care providers.
    No preview · Article · Oct 2015 · Dermatologic Surgery
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    ABSTRACT: Purpose: Immune responses to antigens originating in the CNS are generally attenuated, since collateral damage can have devastating consequences. The significance of this finding for the efficacy of tumor-targeted immunotherapies is largely unknown. Experimental design: The B16 murine melanoma model was used to compare cytotoxic responses against established tumors in the CNS and in the periphery. Cytokine analysis of tissues from brain tumor-bearing mice detected elevated TGF-β secretion from microglia and in the serum and TGF-β signaling blockade reversed tolerance of tumor antigen-directed CD8 T cells. Additionally, a treatment regimen using focal radiation therapy and recombinant Listeria monocytogenes was evaluated for immunologic activity and efficacy in this model. Results: CNS melanomas were more tolerogenic than equivalently progressed tumors outside the CNS as antigen-specific CD8 T cells were deleted and exhibited impaired cytotoxicity. Tumor-bearing mice had elevated serum levels of TGF-β; however, blocking TGF-β signaling with a small molecule inhibitor or a monoclonal antibody did not improve survival. Conversely, tumor antigen-specific vaccination in combination with focal radiation therapy reversed tolerance and improved survival. This treatment regimen was associated with increased polyfunctionality of CD8 T cells, elevated T effector to T regulatory cell ratios and decreased TGF-β secretion from microglia. Conclusions: These data suggest that CNS tumors may impair systemic antitumor immunity and consequently accelerate cancer progression locally as well as outside the CNS. Anti-tumor immunity may be restored by combining vaccination with radiation therapy. These findings are hypothesis-generating and warrant further study in more contemporary melanoma models as well as human trials.
    No preview · Article · Oct 2015 · Clinical Cancer Research
  • Joel Sunshine · Janis M Taube
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    ABSTRACT: Tumors may adopt normal physiologic checkpoints for immunomodulation leading to an imbalance between tumor growth and host surveillance. Antibodies targeting the PD-1/PD-L1 checkpoint have shown dynamic and durable tumor regressions, suggesting a rebalancing of the host-tumor interaction. Nivolumab and pembrolizumab are the anti-PD-1 antibodies that are currently the furthest in clinical development, and anti-PD-L1 agents under investigation include MPDL3280A, MEDI4736, and BMS-936559. These agents have been used to treat advanced melanoma, non-small cell lung cancer, renal cell carcinoma, bladder cancer and Hodgkin lymphoma, amongst other tumor types. In this article, we review the updated response results for early clinical trials, note recent FDA actions regarding this class of agents, and summarize results across trials looking at PD-L1 status as a predictor of response to anti-PD-1/PD-L1. Copyright © 2015 Elsevier Ltd. All rights reserved.
    No preview · Article · Aug 2015 · Current Opinion in Pharmacology
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    ABSTRACT: Decreased hydroxymethylated cytosine (5-hmC) is reported to correlate with melanocyte dysplasia. The purpose of this study was to assess the diagnostic utility of this observation. 5-hmC immunohistochemistry was performed on tissue microarrays containing 171 melanocytic lesions from two different institutions. An immunohistochemical staining score representing the percentage and intensity of nuclear staining was assigned. The performance characteristics of 5-hmC immunohistochemistry for discriminating between a nevus and melanoma were determined. Additional cases of melanoma arising in a nevus (n=8), nodal nevi (n=5), and melanoma micrometastases to a lymph node (n=6) were also assessed. Pronounced 5-hmC loss was observed in melanomas when compared to nevi (mean ± st dev = 6.71 ± 11.78 and 55.19 ± 23.66, respectively, p<0.0001). While the mean immunohistochemical staining score values for melanocytic nevi and melanoma were distinct, there was considerable variability in immunohistochemical staining score within a single diagnostic category. The sensitivity and specificity of this assay for nevus vs. melanoma is 92.74% and 97.78%, respectively. Distinct biphasic staining patterns were observed in cases of melanoma arising in association with a nevus. Relative changes of 5-hmC expression within a single lesion may be more informative than absolute values when using 5-hmC as a diagnostic adjunct. This article is protected by copyright. All rights reserved.
    No preview · Article · Aug 2015 · Journal of Cutaneous Pathology

  • No preview · Article · Aug 2015 · Cancer Research
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    ABSTRACT: Expression of the intermediate filament protein keratin 17 (K17) is robustly upregulated in inflammatory skin diseases and in many tumors originating in stratified and pseudostratified epithelia. We report that autoimmune regulator (Aire), a transcriptional regulator, is inducibly expressed in human and mouse tumor keratinocytes in a K17-dependent manner and is required for timely onset of Gli2-induced skin tumorigenesis in mice. The induction of Aire mRNA in keratinocytes depends on a functional interaction between K17 and the heterogeneous nuclear ribonucleoprotein hnRNP K. Further, K17 colocalizes with Aire protein in the nucleus of tumor-prone keratinocytes, and each factor is bound to a specific promoter region featuring an NF-κB consensus sequence in a relevant subset of K17- and Aire-dependent proinflammatory genes. These findings provide radically new insight into keratin intermediate filament and Aire function, along with a molecular basis for the K17-dependent amplification of inflammatory and immune responses in diseased epithelia.
    No preview · Article · Jul 2015 · Nature Genetics
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    ABSTRACT: Limited adjuvant treatment options exist for patients with high-risk surgically resected melanoma. This first-in-human study investigated the safety, tolerability and immunologic correlates of Melanoma GVAX, a lethally irradiated granulocyte-macrophage colony stimulating factor (GM-CSF)-secreting allogeneic whole-cell melanoma vaccine, administered in the adjuvant setting. Patients with stage IIB-IV melanoma were enrolled following complete surgical resection. Melanoma GVAX was administered intradermally once every 28 days for four cycles, at 5E7 cells/cycle (n = 3), 2E8 cells/cycle (n = 9), or 2E8 cells/cycle preceded by cyclophosphamide 200 mg/m(2) to deplete T regulatory cells (Tregs; n = 8). Blood was collected before each vaccination and at 4 and 6 months after treatment initiation for immunologic studies. Vaccine injection site biopsies and additional blood samples were obtained 2 days after the 1st and 4th vaccines. Among 20 treated patients, 18 completed 4 vaccinations. Minimal treatment-related toxicity was observed. One patient developed vitiligo and patches of white hair during the treatment and follow-up period. Vaccine site biopsies demonstrated complex inflammatory infiltrates, including significant increases in eosinophils and PD-1+ lymphocytes from cycle 1 to cycle 4 (P < 0.05). Serum GM-CSF concentrations increased significantly in a dose-dependent manner 48 h after vaccination (P = 0.0086), accompanied by increased numbers of activated circulating monocytes (P < 0.0001) and decreased percentages of myeloid-derived suppressor cells among monocytes (CD14+ , CD11b+ , HLA-DR low or negative; P = 0.002). Cyclophosphamide did not affect numbers of circulating Tregs. No significant changes in anti-melanoma immunity were observed in peripheral T cells by interferon-gamma ELIPSOT, or immunoglobulins by serum Western blotting. Melanoma GVAX was safe and tolerable in the adjuvant setting. Pharmacodynamic testing revealed complex vaccine site immune infiltrates and an immune-reactive profile in circulating monocytic cell subsets. These findings support the optimization of Melanoma GVAX with additional monocyte and dendritic cell activators, and the potential development of combinatorial treatment regimens with synergistic agents. NCT01435499.
    Preview · Article · Jul 2015 · Journal of Translational Medicine
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    ABSTRACT: Background: In adaptive resistance, tumors use PDL1 induction as a protective mechanism against an antitumor immune response implying underlying immuno-surveillance. By upregulating the expression of ligands for inhibitory receptors on tumor specific lymphocytes in the tumor microenvironment a growing malignancy can avoid immune elimination. Here we report the interaction between PDL1 status and the density of CD8+ at the tumor stromal interface in gastric and gastroesophageal junction adenocarcinomas (G/GEJ). Methods: 34 invasive G/GEJ were stained for PDL1 using the 5H1 clone both at the tumor cell and associated tumor infiltrating lymphocyte/macrophages (TILs/TAMs). Tumors with greater than 5% membranous staining were considered PDL1 positive. TILs/TAMs were scored as no significant staining (0), less than 50% (focal) or greater than 50% (high). CD8+ density was determined using image analysis. Survival was evaluated according to PDL1 and CD8+ status. Results: 4/34 tumors (12%) showed membranous PDL1 expression. 45% of G/GEJ demonstrated PDL1 expression among TILs with 27% showing focal interface expression and 18% high expression. Patients whose tumors were defined as stroma high (CD8+ > 500 cells/m2) had a worse PFS, HR = 3.91 (95% CI: 1.32, 11.59) p = 0.01, and OS, HR = 3.46 (95% CI: 1.09, 10.96) p = 0.03, compared to stroma low (CD8+< 500 cells/mm2). Interestingly in the stroma, 8/9 tumors (89%, CI: 51.8%, 99.7%) with high CD8+ were also positive for PDL1 while only 7/24 (29%, CI: 12.6%, 51.1%) with low CD8+ were PDL1 positive (p = 0.004). PDL1 stromal expression was identified in 33.3% stage I, 53.9% stage II, 37.5% stage III, and 66.7% of stage IV tumors (p = 0.51). Stromal PDL1 expression occurred in 60% of intestinal and 38.5% of diffuse tumors (p = 0.45). Conclusions: PDL1 is expressed on both tumor cells and TILs across all stages and histologies of G/GEJ. Patients with higher CD8+ levels have higher PDL1 expression indicating adaptive resistance is occurring in the tumor microenvironment. Phase II and Phase III clinical trials investigating the efficacy of PD1/PDL1 inhibitors either alone or in combination with CTLA-4 inhibitors are currently ongoing in patients with advanced G/GEJ.
    No preview · Conference Paper · Jun 2015
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    ABSTRACT: The PD-1 pathway, comprising the immune cell co-receptor Programmed Death 1 (PD-1) and its ligands, PD-L1 (B7-H1) and PD-L2 (B7-DC), mediates local immunosuppression in the tumor microenvironment. Drugs designed to block PD-1 or PD-L1 "release the brakes" on anti-tumor immunity and have demonstrated clinical activity in several types of advanced cancers, validating this pathway as a target for cancer therapy. Two such drugs have recently been approved to treat melanoma and lung cancers, and regulatory approvals in first- and second-line settings for additional cancer types are anticipated. The manageable safety profile of PD-1/PD-L1 blocking drugs identifies them as suitable for outpatient administration and the development of combinatorial therapies. Ongoing studies aim to identify biomarkers to guide patient selection, which would further improve the risk:benefit ratio for these drugs. Copyright © 2015 Elsevier Inc. All rights reserved.
    No preview · Article · Jun 2015 · Seminars in Oncology
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    ABSTRACT: Background: Somatic mutations have the potential to encode "non-self" immunogenic antigens. We hypothesized that tumors with a large number of somatic mutations due to mismatch-repair defects may be susceptible to immune checkpoint blockade. Methods: We conducted a phase 2 study to evaluate the clinical activity of pembrolizumab, an anti-programmed death 1 immune checkpoint inhibitor, in 41 patients with progressive metastatic carcinoma with or without mismatch-repair deficiency. Pembrolizumab was administered intravenously at a dose of 10 mg per kilogram of body weight every 14 days in patients with mismatch repair-deficient colorectal cancers, patients with mismatch repair-proficient colorectal cancers, and patients with mismatch repair-deficient cancers that were not colorectal. The coprimary end points were the immune-related objective response rate and the 20-week immune-related progression-free survival rate. Results: The immune-related objective response rate and immune-related progression-free survival rate were 40% (4 of 10 patients) and 78% (7 of 9 patients), respectively, for mismatch repair-deficient colorectal cancers and 0% (0 of 18 patients) and 11% (2 of 18 patients) for mismatch repair-proficient colorectal cancers. The median progression-free survival and overall survival were not reached in the cohort with mismatch repair-deficient colorectal cancer but were 2.2 and 5.0 months, respectively, in the cohort with mismatch repair-proficient colorectal cancer (hazard ratio for disease progression or death, 0.10 [P<0.001], and hazard ratio for death, 0.22 [P=0.05]). Patients with mismatch repair-deficient noncolorectal cancer had responses similar to those of patients with mismatch repair-deficient colorectal cancer (immune-related objective response rate, 71% [5 of 7 patients]; immune-related progression-free survival rate, 67% [4 of 6 patients]). Whole-exome sequencing revealed a mean of 1782 somatic mutations per tumor in mismatch repair-deficient tumors, as compared with 73 in mismatch repair-proficient tumors (P=0.007), and high somatic mutation loads were associated with prolonged progression-free survival (P=0.02). Conclusions: This study showed that mismatch-repair status predicted clinical benefit of immune checkpoint blockade with pembrolizumab. (Funded by Johns Hopkins University and others; ClinicalTrials.gov number, NCT01876511.).
    Full-text · Article · May 2015 · New England Journal of Medicine
  • Sneha Berry · Janis M. Taube
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    ABSTRACT: Oncogenic driver mutations in several tumor types promote constitutive PD-L1 expression, a crucial ligand in PD-1-mediated immune escape. Our studies in melanoma suggest a different mechanism-one of “adaptive immune resistance” where PD-L1 expression is primarily driven by cytokine induction and is independent of BRAF mutational status.
    No preview · Article · May 2015 · OncoImmunology
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    ABSTRACT: Blocking the immunosuppressive PD-1/PD-L1 pathway has anti-tumor activity in multiple cancer types, and PD-L1 expression on tumor cells and infiltrating myeloid cells correlates with the likelihood of response. We previously found that IFNG (interferon-gamma) was over-expressed by TILs in PD-L1+ vs. PD-L1(-) melanomas, creating adaptive immune resistance by promoting PD-L1 display. The current study was undertaken to identify additional factors in the PD-L1+ melanoma microenvironment coordinately contributing to immunosuppression. Archived, formalin-fixed paraffin-embedded melanoma specimens were assessed for PD-L1 protein expression at the tumor cell surface with immunohistochemistry (IHC). Whole genome expression analysis, quantitative (q)RT-PCR, immunohistochemistry, and functional in vitro validation studies were employed to assess factors differentially expressed in PD-L1+ versus PD-L1(-) melanomas. Functional annotation clustering based on whole genome expression profiling revealed pathways up-regulated in PD-L1+ melanomas, involving immune cell activation, inflammation, and antigen processing and presentation. Analysis by qRT-PCR demonstrated over-expression of functionally related genes in PD-L1+ melanomas, involved in CD8+ T cell activation (CD8A, IFNG, PRF1, CCL5), antigen presentation (CD163, TLR3, CXCL1, LYZ), and immunosuppression [PDCD1 (PD-1), CD274 (PD-L1), LAG3, IL10]. Functional studies demonstrated that some factors, including IL-10 and IL-32-gamma, induced PD-L1 expression on monocytes but not tumor cells. These studies elucidate the complexity of immune checkpoint regulation in the tumor microenvironment, identifying multiple factors likely contributing to coordinated immunosuppression. These factors may provide tumor escape mechanisms from anti-PD-1/PD-L1 therapy, and should be considered for co-targeting in combinatorial immunomodulation treatment strategies. Copyright © 2015, American Association for Cancer Research.
    Full-text · Article · May 2015 · Clinical Cancer Research
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    Preview · Article · Apr 2015 · The Journal of Urology
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    Full-text · Article · Apr 2015 · The Journal of Urology
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    ABSTRACT: To evaluate programmed death ligand 1 (PD-L1) expression in urothelial carcinoma of the bladder in relationship with tumor-infiltrating CD8+ T cells. Tissue microarrays were prepared from 56 cystectomy specimens performed at our hospital (1994-2002). PD-L1 immunoexpression was assessed using the murine antihuman PD-L1 monoclonal antibody 5H1. Extent of membranous PD-L1 expression was assigned in each spot. Spots showing ≥5% expression were considered positive. Average PD-L1 expression per tumor was also calculated (5% positivity cutoff). "High CD8 density" was defined as the presence of ≥60 CD8+ intraepithelial lymphocytes per high power field in a given spot. A tumor was considered high density if ≥50% of its spots were of high density. PD-L1 expression was positive in approximately 20% of tumors. None of the benign urothelium spots expressed PD-L1. High CD8 density was observed in approximately 20% of cases. CD8 density did not correlate with PD-L1 expression. Overall survival (OS) and disease-specific survival (DSS) rates were 14% and 28%, respectively (median follow-up, 31.5 months). PD-L1 expression was associated with age at cystectomy (P = .01). Remaining clinicopathologic parameters were not associated with PD-L1 expression or CD8 density. High CD8 density was associated with favorable OS (P = .02) and DSS (P = .02). The same was true when CD8 density was adjusted for demographic and clinicopathologic parameters. There was no correlation between PD-L1 expression and outcome. High intratumoral CD8+ T cell density is associated with better OS and DSS in invasive urothelial carcinoma of the bladder. We found no correlation between PD-L1 expression and outcome. Copyright © 2015 Elsevier Inc. All rights reserved.
    No preview · Article · Mar 2015 · Urology

Publication Stats

5k Citations
526.90 Total Impact Points

Institutions

  • 2008-2015
    • Johns Hopkins University
      • • Department of Pathology
      • • Department of Surgery
      Baltimore, Maryland, United States
  • 2006-2015
    • Johns Hopkins Medicine
      • • Department of Dermatology
      • • Department of Pathology
      Baltimore, Maryland, United States
  • 2010
    • Washington University in St. Louis
      San Luis, Missouri, United States
    • Stanford University
      Stanford, California, United States