Janis M Taube

Johns Hopkins University, Baltimore, Maryland, United States

Are you Janis M Taube?

Claim your profile

Publications (54)286.06 Total impact

  • [Show abstract] [Hide abstract]
    ABSTRACT: PD-L1 expression in melanoma correlates with response to PD-1 pathway blocking antibodies. Aberrant tumor cell PD-L1 expression may be oncogene-driven and/or induced by interferon-gamma (IFN-g). Melanomas express PD-L1 in association with tumor infiltrating lymphocytes (TILs), but the potential contribution of the BRAF V600E mutation (BRAFmut) to induced PD-L1 expression has not been determined. Fifty-two archival melanocytic lesions were simultaneously assessed for PD-L1 expression, TIL infiltration and BRAFmut. IFN-g-induced PD-L1 expression in cultured melanomas was also assessed according to BRAF status. Melanocyte PD-L1 expression was observed in 40% of specimens, and BRAFmut was observed in 42% of specimens, but there was no significant concordance between these variables. Almost all melanocytes displaying PD-L1 expression were observed adjacent to TILs, irrespective of BRAF status. TIL(-) lesions were not more likely to be associated with BRAFmut, compared to TIL(+) lesions. Baseline expression of PD-L1 by melanoma cell lines was virtually nil regardless of BRAFmut status, and the intensity of interferon-induced PD-L1 expression in melanoma cell lines likewise did not correlate with BRAF mutational status. PD-L1 expression in melanocytic lesions does not correlate with the BRAFmut. Thus, distinct populations of melanoma patients will likely benefit from BRAF inhibitors vs. PD-1 pathway blockade.
    Cancer immunology research. 11/2014;
  • [Show abstract] [Hide abstract]
    ABSTRACT: We examined the immune microenvironment of primary colorectal cancer (CRC) using immunohistochemistry, laser capture microdissection/qRT-PCR, flow cytometry and functional analysis of tumor infiltrating lymphocytes. A subset of CRC displayed high infiltration with activated CD8+ CTL as well as activated Th1 cells characterized by IFN-γ production and the Th1 transcription factor Tbet. Parallel analysis of tumor genotypes revealed that virtually all of the tumors with this active Th1/CTL microenvironment had defects in mismatch repair, as evidenced by microsatellite instability (MSI). Counterbalancing this active Th1/CTL microenvironment, MSI tumors selectively demonstrated highly up-regulated expression of multiple immune checkpoints, including five - PD-1, PD-L1, CTLA-4, LAG-3 and IDO - currently being targeted clinically with inhibitors. These findings link tumor genotype with the immune microenvironment, and explain why MSI tumors are not naturally eliminated despite a hostile Th1/CTL microenvironment. They further suggest that blockade of specific checkpoints may be selectively efficacious in the MSI subset of CRC.
    Cancer Discovery 10/2014; · 15.93 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Chordomas are rare malignant tumors that are postulated to arise from remnants of the notochord. Currently, the interaction between chordomas and the host immune system is poorly understood. The checkpoint protein, PD-1 is expressed by circulating lymphocytes and is a marker of activation and exhaustion. Its ligands, PD-L1 (B7-H1, CD274) and PD-L2 (B7-DC, CD273), are expressed on a variety of human cancers; however this pathway has not been previously reported in chordomas. We used flow cytometric and RT-PCR analysis in three established primary and recurrent chordoma cell lines (U-CH1, U-CH2, and JHC7) as well as immunohistochemical analysis of chordoma tissues from 10 patients to identify and localize expression of PD-1 pathway proteins. PD-1 ligands are not constitutively expressed by chordoma cells, but their expression is induced in the setting of pro-inflammatory cytokines in all cell lines examined. In paraffin embedded tissues, we found that tumor infiltrating lymphocytes expressed PD-1 in 3/6 cases. We also found that, although chordoma cells did not express significant levels of PD-L1, PD-L1 expression was observed on tumor-infiltrating macrophages and tumor infiltrating lymphocytes. Our study suggests that PD-1, PD-L1, and PD-L2 are present in the microenvironment of a subset of chordomas analyzed. Future studies are needed to evaluate the contribution of the PD-1 pathway to the immunosuppressive microenvironment of chordomas.
    Journal of Neuro-Oncology 10/2014; · 2.79 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Primary effusion lymphoma (PEL) is a rare and aggressive lymphoma that arises in the context of immunosuppression and is characterized by co-infection with Epstein-Barr virus (EBV) and Human Herpesvirus-8/Kaposi sarcoma-associated herpesvirus (HHV-8/KSHV). It was originally described as arising in body cavity effusions, but presentation as a mass lesion (extracavitary PEL) is now recognized. Here we describe a case of PEL with an initial presentation as an intravascular lymphoma with associated skin lesions. The patient was a 53 year-old man with HIV/AIDS who presented with fevers, weight loss, and skin lesions concerning for Kaposi sarcoma (KS). A skin biopsy revealed no evidence of KS; however, dermal vessels contained large atypical cells that expressed CD31 and plasma cell markers but lacked most B and T cell antigens. The atypical cells expressed EBV and HHV-8. The patient subsequently developed a malignant pleural effusion containing the same neoplastic cell population. The findings in this case highlight the potential for unusual intravascular presentations of PEL in the skin as well as the importance of pursuing microscopic diagnosis of skin lesions in immunosuppressed patients.
    Journal of Cutaneous Pathology 10/2014; · 1.56 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Objectives BRAF mutations have substantial therapeutic, diagnostic, and prognostic significance, so detecting and specifying them is an important part of the workload of molecular pathology laboratories. Pyrosequencing assays are well suited for this analysis but can produce complex results. Therefore, we introduce a pyrosequencing lookup table based on Pyromaker that assists the user in generating hypotheses for solving complex pyrosequencing results. Methods The lookup table contains all known mutations in the sequenced region and the positions in the dispensation sequence at which changes would occur with those mutations. We demonstrate the lookup table using a homebrew dispensation sequence for BRAF codons 596 to 605 as well as a commercially available kit-based dispensation sequence for codons 599 to 600. Results These results demonstrate that the homebrew dispensation sequence unambiguously identifies all known BRAF mutations in this region, whereas the kit-based dispensation sequence has one unresolvable degeneracy that could be solved with the addition of two injections. Conclusions Using the lookup table and confirmatory virtual pyrogram, we unambiguously solved clinical pyrograms of the complex mutations V600K (c.1798_1799delGTinsAA), V600R (c.1798_1799delGTinsAG), V600D (c.1799_1800delTGinsAT), V600E (c.1799_1800delTGinsAA), and V600_K601delinsE (c.1799_1801delTGA). In addition, we used the approach to hypothesize and confirm a new mutation in human melanoma, V600_K601delinsEI (c.1799_1802delTGAAinsAAAT).
    American Journal of Clinical Pathology 05/2014; 141(5):639-47. · 2.88 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Immunomodulatory drugs differ in mechanism-of-action from directly cytotoxic cancer therapies. Identifying factors predicting clinical response could guide patient selection and therapeutic optimization. Patients (N=41) with melanoma, non-small cell lung carcinoma (NSCLC), renal cell carcinoma (RCC), colorectal carcinoma or castration-resistant prostate cancer were treated on an early phase trial of anti-PD-1 (nivolumab) at one institution and had evaluable pre-treatment tumor specimens. Immunoarchitectural features including PD-1, PD-L1, and PD-L2 expression, patterns of immune cell infiltration, and lymphocyte subpopulations, were assessed for interrelationships and potential correlations with clinical outcomes. Membranous (cell surface) PD-L1 expression by tumor cells and immune infiltrates varied significantly by tumor type and was most abundant in melanoma, NSCLC, and RCC. In the overall cohort, PD-L1 expression was geographically associated with infiltrating immune cells (p<0.001), although lymphocyte-rich regions were not always associated with PD-L1 expression. Expression of PD-L1 by tumor cells and immune infiltrates was significantly associated with expression of PD-1 on lymphocytes. PD-L2, the second ligand for PD-1, was associated with PD-L1 expression. Tumor cell PD-L1 expression correlated with objective response to anti-PD-1 therapy, when analyzing either the specimen obtained closest to therapy or the highest scoring sample among multiple biopsies from individual patients. These correlations were stronger than borderline associations of PD-1 expression or the presence of intratumoral immune cell infiltrates with response. Tumor PD-L1 expression reflects an immune-active microenvironment and, while associated other immunosuppressive molecules including PD-1 and PD-L2, is the single factor most closely correlated with response to anti-PD-1 blockade.
    Clinical Cancer Research 04/2014; · 8.19 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Basal cell carcinoma (BCC) of the vulva is rare and may be confused with the much more commonly encountered high-risk human papillomavirus (HPV)-related basaloid squamous cell carcinoma (SCC). The HPV status of BCCs is not well established. This study assesses the utility of p16 and BerEP4 expression patterns and high-risk HPV detection for distinction of these tumors. Thirteen cases of vulvar BCC were analyzed by immunohistochemistry for p16 and BerEP4 expression. HPV status was assessed by in situ hybridization (ISH) with a high-risk HPV wide-spectrum probe and HPV 16 and 18 type-specific probes. All tumors (13/13) demonstrated patchy p16 positivity, with <50% of tumor cells expressing p16 in all cases. None demonstrated the diffuse p16 expression characteristic of high-risk HPV-associated lesions. No high-risk HPV was detected by ISH (0/13). Eleven of 13 (85%) vulvar BCCs showed diffuse, intense expression of BerEP4. The 2 BerEP4-negative cases were notably squamatized. The lack of diffuse p16 expression and failure to detect high-risk HPV by ISH in vulvar BCCs indicate that these tumors are unrelated to high-risk HPV. Thus, these ancillary techniques, particularly p16 immunohistochemistry, are useful for distinguishing vulvar BCCs from basaloid forms of high-risk HPV-related vulvar SCC. BerEP4 expression can help in distinction of these tumors except in cases of BCC with extensive squamatization. Distinction of vulvar BCC from basaloid SCC is important because of differences in extent of surgical treatment for these entities.
    The American journal of surgical pathology 04/2014; 38(4):542-7. · 4.59 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Background: Treatment with a blocking αPD-1 antibody recently showed clinical efficacy for various tumors types. In this study, we characterized the expression profile of PD-1/PD-L1 and the potential of PD-1 blockade in human papilloma virus (HPV)-negative head and neck squamous cell carcinoma (HNSCC).Methods: Lymphocytes from peripheral blood, draining lymph nodes and the tumor were phenotyped for PD-1 expression, and their proliferative activity was assessed in the presence of blocking αPD-1 treatment. Primary tumor expression of PD-L1 was also analyzed using immunohistochemistry.Results: Lymphocyte PD-1 expression was abundant with highest expression in the tumor and in vitro mixed lymphocyte reaction demonstrated that PD-1 blockade could induce T cell proliferation. Furthermore, tumor cells were found to have three distinct patterns of PD-L1 expression with over 82% of the specimens demonstrating strong PD-L1 positivity.Conclusions: Our data strongly supports the use of αPD-1 blockade in HPV-negative HNSCC patients that are refractory to standard treatments. Head Neck, 2014
    Head & Neck 04/2014; · 2.83 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Detection of BRAF mutations is an established standard of care to predict small-molecule inhibitor (vemurafenib) response in metastatic melanoma. Molecular assays should be designed to detect not only the most common p.V600E mutation, but also p.V600K and other non-p.V600E mutations. The purpose of this study was to assess if tumor cellularity can function as a quality assurance (QA) measure in molecular diagnostics. Potential causes of discrepancy between the observed and predicted mutant allele percentage were also explored. We correlated pathologist-generated estimates of tumor cellularity versus mutant allele percentage via pyrosequencing as a QA measure for BRAF mutation detection in formalin-fixed, paraffin-embedded melanoma specimens. BRAF mutations were seen in 27/62 (44 %) specimens, with 93 % p.V600E and 7 % non-p.V600E. Correlation between p.V600E mutant percentage and tumor cellularity was poor-moderate (r = -0.02; p = 0.8), primarily because six samples showed a low p.V600E signal despite high tumor cellularity. A QA investigation revealed that our initial pyrosequencing assay showed a false positive, weak p.V600E signal in specimens with a p.V600K mutation. A redesigned assay detected BRAF mutations in 50/131 (38 %) specimens, including 30 % non-p.V600E. This revised assay showed strong correlation between p.V600E BRAF mutant percentage and tumor cellularity (r = 0.76; p ≤ 0.01). Re-evaluation of the previously discordant samples by the revised assay confirmed a high level of p.V600K mutation in five specimens. Pathologists play important roles in molecular diagnostics, beyond identification of correct cells for testing. Accurate evaluation of tumor cellularity not only ensures sufficient material for required analytic sensitivity, but also provides an independent QA measure of the molecular assays.
    Molecular diagnosis & therapy. 03/2014;
  • [Show abstract] [Hide abstract]
    ABSTRACT: Programmed cell death 1 (PD-1) is an inhibitory receptor expressed by activated T cells that downmodulates effector functions and limits the generation of immune memory. PD-1 blockade can mediate tumor regression in a substantial proportion of patients with melanoma, but it is not known whether this is associated with extended survival or maintenance of response after treatment is discontinued. Patients with advanced melanoma (N = 107) enrolled between 2008 and 2012 received intravenous nivolumab in an outpatient setting every 2 weeks for up to 96 weeks and were observed for overall survival, long-term safety, and response duration after treatment discontinuation. Median overall survival in nivolumab-treated patients (62% with two to five prior systemic therapies) was 16.8 months, and 1- and 2-year survival rates were 62% and 43%, respectively. Among 33 patients with objective tumor regressions (31%), the Kaplan-Meier estimated median response duration was 2 years. Seventeen patients discontinued therapy for reasons other than disease progression, and 12 (71%) of 17 maintained responses off-therapy for at least 16 weeks (range, 16 to 56+ weeks). Objective response and toxicity rates were similar to those reported previously; in an extended analysis of all 306 patients treated on this trial (including those with other cancer types), exposure-adjusted toxicity rates were not cumulative. Overall survival following nivolumab treatment in patients with advanced treatment-refractory melanoma compares favorably with that in literature studies of similar patient populations. Responses were durable and persisted after drug discontinuation. Long-term safety was acceptable. Ongoing randomized clinical trials will further assess the impact of nivolumab therapy on overall survival in patients with metastatic melanoma.
    Journal of Clinical Oncology 03/2014; · 17.88 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Intravascular lymphomas are rare and aggressive hematolymphoid tumors. Here, we describe a human herpesvirus type-8 (HHV-8)/Kaposi sarcoma-associated herpesvirus-positive and Epstein-Barr virus (EBV)-positive intravascular lymphoma. The patient was a 59-year-old human immunodeficiency virus-positive man who presented with diarrhea, abdominal pain, fevers, night sweats, and weight loss. Radiographic studies of the abdomen and pelvis revealed numerous subcentimeter nodules within the subcutaneous fat that lacked connection to the skin. An excisional biopsy demonstrated large atypical cells within vessels in the deep subcutaneous fat, and many of the vessels contained extensive organizing thrombi. The atypical cells lacked strong expression of most B-cell markers but were positive for MUM-1 and showed partial expression of several T-cell markers. An immunohistochemical stain for HHV-8 and an in situ hybridization for EBV were both positive in the neoplastic cells. The disease had a rapidly progressive and fatal course. This lymphoma appears to represent an entirely intravascular form of primary effusion lymphoma and highlights the propensity for HHV-8 and EBV-positive lymphoid neoplasms to show aberrant expression of T-cell markers, illustrates the utility of skin biopsies for the diagnosis of intravascular lymphoma, and suggests that biopsies to evaluate for intravascular lymphoma should be relatively deep and include subcutaneous fat.
    The American journal of surgical pathology 03/2014; 38(3):426-32. · 4.59 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Chordomas constitute a slowly growing malignant tumor of mesenchymal origin. They grow along the craniospinal axis but they are much more frequent at its two ends (skull base and sacral region). They can be locally invasive and not infrequently give remote metastases. Despite aggressive therapy that consists of en block resection of the tumor with or without radiation the patients experience very often recurrence with an overall 10 year survival rate of 39%. Despite an extensive genetic analysis, gene expression and molecular analysis of possible cellular pathways involved in the chordoma progression, very little is known about the interaction of chordomas with the immune system. The lack of a sufficient mouse model that recapitulates the human disease and the rarity of these tumors among the general population have left unexplored the immune system reaction to chordomas. The immune checkpoints are a group of surface proteins and secreted molecules that inhibit the activation and expansion of immune cells towards a robust antitumor response. Programmed death 1 (PD-1) with its two ligands (PDL1, PDL2) are an example of immune checkpoint inhibitors that has been shown to play a crucial role in the progression of other types of cancer. We explored the potential of PD-1 - PDL1, PDL2 pathway in the involvement of immunosuppression in chordomas. For this purpose we used established chordoma cell lines and chordoma human samples to evaluate the expression of these surface markers in chordomas. We also sought to assess the inducible expression of PDL1, PDL2 in human chordoma cell lines to establish a mechanistic basis by which these two molecules may be differentially expressed in human chordoma samples.
    Society of Neurooncology (SNO/WFNO), San Francisco; 11/2013
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Innovative therapies are needed for advanced Non-Small Cell Lung Cancer (NSCLC). We have undertaken a genomics based, hypothesis driving, approach to query an emerging potential that epigenetic therapy may sensitize to immune checkpoint therapy targeting PD-L1/PD-1 interaction. NSCLC cell lines were treated with the DNA hypomethylating agent azacytidine (AZA - Vidaza) and genes and pathways altered were mapped by genome-wide expression and DNA methylation analyses. AZA-induced pathways were analyzed in The Cancer Genome Atlas (TCGA) project by mapping the derived gene signatures in hundreds of lung adeno (LUAD) and squamous cell carcinoma (LUSC) samples. AZA up-regulates genes and pathways related to both innate and adaptive immunity and genes related to immune evasion in a several NSCLC lines. DNA hypermethylation and low expression of IRF7, an interferon transcription factor, tracks with this signature particularly in LUSC. In concert with these events, AZA up-regulates PD-L1 transcripts and protein, a key ligand-mediator of immune tolerance. Analysis of TCGA samples demonstrates that a significant proportion of primary NSCLC have low expression of AZA-induced immune genes, including PD-L1. We hypothesize that epigenetic therapy combined with blockade of immune checkpoints - in particular the PD-1/PD-L1 pathway - may augment response of NSCLC by shifting the balance between immune activation and immune inhibition, particularly in a subset of NSCLC with low expression of these pathways. Our studies define a biomarker strategy for response in a recently initiated trial to examine the potential of epigenetic therapy to sensitize patients with NSCLC to PD-1 immune checkpoint blockade.
    Oncotarget 10/2013; · 6.63 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Merkel cell carcinoma (MCC) is a lethal, virus-associated cancer that lacks effective therapies for advanced disease. Agents blocking the PD-1/PD-L1 pathway have demonstrated objective, durable tumor regressions in patients with advanced solid malignancies and efficacy has been linked to PD-L1 expression in the tumor microenvironment. To investigate whether MCC might be a target for PD-1/PD-L1 blockade, we examined MCC PD-L1 expression, its association with tumor-infiltrating lymphocytes (TILs), Merkel cell polyomavirus (MCPyV), and overall survival. Sixty-seven MCC specimens from 49 patients were assessed with immunohistochemistry for PD-L1 expression by tumor cells and TILs, and immune infiltrates were characterized phenotypically. Tumor cell and TIL PD-L1 expression were observed in 49% and 55% of patients, respectively. In specimens with PD-L1(+) tumor cells, 97% (28/29) demonstrated a geographic association with immune infiltrates. Among specimens with moderate-severe TIL intensities, 100% (29/29) demonstrated PD-L1 expression by tumor cells. Significant associations were also observed between the presence of MCPyV DNA, a brisk inflammatory response, and tumor cell PD-L1 expression: MCPyV(-) tumor cells were uniformly PD-L1(-). Taken together, these findings suggest that a local tumor-specific and potentially MCPyV-specific immune response drives tumor PD-L1 expression, similar to previous observations in melanoma and head and neck squamous cell carcinomas. In multivariate analyses, PD-L1(-) MCCs were independently associated with worse overall survival (hazard ratio 3.12; 95% CI, 1.28-7.61; p=0.012). These findings suggest that an endogenous immune response promotes PD-L1 expression in the MCC microenvironment when MCPyV is present, and provide a rationale for investigating therapies blocking PD-1/PD-L1 for patients with MCC.
    Cancer immunology research. 07/2013; 1.
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: The B7/CD28 family has profound modulatory effects in immune responses and constitutes an important target for the development of novel therapeutic drugs against human diseases. Here we describe a new CD28 homologue (CD28H) that has unique functions in the regulation of the human immune response and is absent in mice. CD28H is constitutively expressed on all naive T cells. Repetitive antigenic exposure, however, induces a complete loss of CD28H on many T cells, and CD28H negative T cells have a phenotype of terminal differentiation and senescence. After extensive screening in a receptor array, a B7-like molecule, B7 homologue 5 (B7-H5), was identified as a specific ligand for CD28H. B7-H5 is constitutively found in macrophages and could be induced on dendritic cells. The B7-H5/CD28H interaction selectively costimulates human T-cell growth and cytokine production via an AKT-dependent signalling cascade. Our study identifies a novel costimulatory pathway regulating human T-cell responses.
    Nature Communications 06/2013; 4:2043. · 10.74 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: : Dermal-based combined squamous and melanocytic neoplasms are emerging clinicopathologic entities that tend to appear on sun-exposed areas of elderly patients. The biologic behavior of such cutaneous neoplasms remains uncertain because of their rarity. Histopathologic differential includes the following diagnostic entities: (1) dermal squamomelanocytic tumor, (2) melanocytic matricoma, and (3) rare histologic variant of pilomatrical carcinoma, the so-called pilomatrical carcinoma with intralesional melanocytes. Herein, we present a novel case of locally invasive dermal squamomelanocytic tumor. A 72-year-old man presented with a pigmented papule on nasal ala that was clinically concerning for basal cell carcinoma. Histopathologic evaluation demonstrated atypical melanocytic cells architecturally and intimately intermixed with single units and clusters of atypical squamous cells. Most notable feature of this case is focal matrical differentiation and locally invasive tumor growth, characterized by multifocal perineural invasion.
    The American Journal of dermatopathology 06/2013; 35(4):e72-6. · 1.30 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Poly(ethylene glycol) (PEG)-based hydrogels are extensively used in a variety of biomedical applications, due to ease of synthesis and tissue-like properties. Recently there have been varied reports regarding PEG hydrogel's degradation kinetics and in vivo host response. In particular, these studies suggest that the surrounding tissue environment could play a critical role in defining the inflammatory response and degradation kinetics of PEG implants. In the present study we demonstrated a potential mechanism of PEG hydrogel degradation, and in addition we show potential evidence of the role of the surrounding tissue environment on producing variable inflammatory responses. Copyright © 2013 John Wiley & Sons, Ltd.
    Journal of Tissue Engineering and Regenerative Medicine 03/2013; · 4.43 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Cathepsin K is consistently and diffusely expressed in alveolar soft part sarcoma (ASPS) and a subset of translocation renal cell carcinomas (RCCs). However, cathepsin K expression in human neoplasms has not been systematically analyzed. We constructed tissue microarrays (TMA) from a wide variety of human neoplasms, and performed cathepsin K immunohistochemistry (IHC). Only 2.7% of 1,140 carcinomas from various sites exhibited cathepsin K labeling, thus suggesting that among carcinomas, cathepsin K labeling is highly specific for translocation RCC. In contrast to carcinomas, cathepsin K labeling was relatively common (54.6%) in the 414 mesenchymal lesions studied, including granular cell tumor, melanoma, and histiocytic lesions, but not paraganglioma, all of which are in the morphologic differential diagnosis of ASPS. Cathepsin K IHC can be helpful in distinguishing ASPS and translocation RCC from some but not all of the lesions in their differential diagnosis.
    American Journal of Clinical Pathology 02/2013; 139(2):151-9. · 2.88 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Human papillomavirus-associated head and neck squamous cell carcinomas (HPV-HNSCC) originate in the tonsils, the major lymphoid organ that orchestrates immunity to oral infections. Despite its location, the virus escapes immune elimination during malignant transformation and progression. Here, we provide evidence for the role of the PD-1:PD-L1 pathway in HPV-HNSCC immune resistance. We demonstrate membranous expression of PD-L1 in the tonsillar crypts, the site of initial HPV infection. In HPV-HNSCCs that are highly infiltrated with lymphocytes, PD-L1 expression on both tumor cells and CD68+ tumor associated macrophages (TAMs) is geographically localized to sites of lymphocyte fronts, while the majority of CD8+ tumor infiltrating lymphocytes (TILs) express high levels of PD-1, the inhibitory PD-L1 receptor. Significant levels of mRNA for interferon-γ (IFN-γ, a major cytokine inducer of PD-L1 expression, were found in HPV+ PD-L1(+) tumors. Our findings support the role of the PD-1:PD-L1 interaction in creating an "immune-privileged" site for initial viral infection and subsequent adaptive immune resistance once tumors are established and suggest a rationale for therapeutic blockade of this pathway in patients with HPV-HNSCC.
    Cancer Research 01/2013; · 9.28 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: B7-H1/PD-L1, a member of the B7 family of immune-regulatory cell-surface proteins, plays an important role in the negative regulation of cell-mediated immune responses through its interaction with its receptor, programmed death-1 (PD-1) (1,2). Overexpression of B7-H1 by tumor cells has been noted in a number of human cancers, including melanoma, glioblastoma, and carcinomas of the lung, breast, colon, ovary, and renal cells, and has been shown to impair anti-tumor T-cell immunity(3-8). Recently, B7-H1 expression by pancreatic adenocarcinoma tissues has been identified as a potential prognostic marker(9,10). Additionally, blockade of B7-H1 in a mouse model of pancreatic cancer has been shown to produce an anti-tumor response(11). These data suggest the importance of B7-H1 as a potential therapeutic target. Anti-B7-H1 blockade antibodies are therefore being tested in clinical trials for multiple human solid tumors including melanoma and cancers of lung, colon, kidney, stomach and pancreas(12). In order to eventually be able to identify the patients who will benefit from B7-H1 targeting therapies, it is critical to investigate the correlation between expression and localization of B7-H1 and patient response to treatment with B7-H1 blockade antibodies. Examining the expression of B7-H1 in human pancreatic adenocarcinoma tissues through immunohistochemistry will give a better understanding of how this co-inhibitory signaling molecule contributes to the suppression of antitumor immunity in the tumor's microenvironment. The anti-B7-H1 monoclonal antibody (clone 5H1) developed by Chen and coworkers has been shown to produce reliable staining results in cryosections of multiple types of human neoplastic tissues(4,8), but staining on paraffin-embedded slides had been a challenge until recently(13-18). We have developed the B7-H1 staining protocol for paraffin-embedded slides of pancreatic adenocarcinoma tissues. The B7-H1 staining protocol described here produces consistent membranous and cytoplasmic staining of B7-H1 with little background.
    Journal of Visualized Experiments 01/2013;

Publication Stats

2k Citations
286.06 Total Impact Points

Institutions

  • 2011–2014
    • Johns Hopkins University
      Baltimore, Maryland, United States
  • 2006–2014
    • Johns Hopkins Medicine
      • • Department of Dermatology
      • • Department of Pathology
      Baltimore, Maryland, United States
  • 2010
    • Stanford Medicine
      • Department of Pathology
      Stanford, California, United States