Publications by authors named "J David Peske"

12 Publications

  • Page 1 of 1

Comparative Transcriptomic Analysis Identifies a Range of Immunologically Related Functional Elaborations of Lymph Node Associated Lymphatic and Blood Endothelial Cells.

Front Immunol 2019 16;10:816. Epub 2019 Apr 16.

Department of Microbiology, Immunology, and Cancer Biology, Carter Immunology Center, University of Virginia School of Medicine, Charlottesville, VA, United States.

Lymphatic and blood vessels are formed by specialized lymphatic endothelial cells (LEC) and blood endothelial cells (BEC), respectively. These endothelial populations not only form peripheral tissue vessels, but also critical supporting structures in secondary lymphoid organs, particularly the lymph node (LN). Lymph node LEC (LN-LEC) also have been shown to have important immunological functions that are not observed in LEC from tissue lymphatics. LN-LEC can maintain peripheral tolerance through direct presentation of self-antigen via MHC-I, leading to CD8 T cell deletion; and through transfer of self-antigen to dendritic cells for presentation via MHC-II, resulting in CD4 T cell anergy. LN-LEC also can capture and archive foreign antigens, transferring them to dendritic cells for maintenance of memory CD8 T cells. The molecular basis for these functional elaborations in LN-LEC remain largely unexplored, and it is also unclear whether blood endothelial cells in LN (LN-BEC) might express similar enhanced immunologic functionality. Here, we used RNA-Seq to compare the transcriptomic profiles of freshly isolated murine LEC and BEC from LN with one another and with freshly isolated LEC from the periphery (diaphragm). We show that LN-LEC, LN-BEC, and diaphragm LEC (D-LEC) are transcriptionally distinct from one another, demonstrating both lineage and tissue-specific functional specializations. Surprisingly, tissue microenvironment differences in gene expression profiles were more numerous than those determined by endothelial cell lineage specification. In this regard, both LN-localized endothelial cell populations show a variety of functional elaborations that suggest how they may function as antigen presenting cells, and also point to as yet unexplored roles in both positive and negative regulation of innate and adaptive immune responses. The present work has defined in depth gene expression differences that point to functional specializations of endothelial cell populations in different anatomical locations, but especially the LN. Beyond the analyses provided here, these data are a resource for future work to uncover mechanisms of endothelial cell functionality.
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http://dx.doi.org/10.3389/fimmu.2019.00816DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6478037PMC
September 2020

Integrating histopathology, immune biomarkers, and molecular subgroups in solid cancer: the next step in precision oncology.

Virchows Arch 2019 Apr 10;474(4):463-474. Epub 2019 Jan 10.

INSERM, UMR_S 1138, Centre de Recherche des Cordeliers, Team "Cancer, immune control and escape", 75006, Paris, France.

For many years, the gold standard cancer grading and staging had focused on the characteristics of the cancer cells and often disregarded the non-tumoral cell compartments. The expansion of research on the tumor immune microenvironment, the successes and dissemination of immunotherapies to treat cancer, and the open access to large -omic databases have allowed the development of novel powerful immune-based prognostic and theranostic biomarkers. Although they often correlate with histopathologic characteristics and TNM staging, in many instances, they are independently associated with, and potentially superior predictors of, the patient's prognosis and response to immunotherapies. As pathologists in the era of precision medicine, we are uniquely positioned to participate in the integration of these histologic and molecular features of the tumor microenvironment to provide the best prognostic information to clinicians and patients. In this review, we summarize some of the most important immune-related prognostic biomarkers in solid cancer, how they integrate with traditional histopathologic (i.e., staging and grading) and novel molecular stratification systems, and their potential role as predictors to response to agents blocking the PD-1/PD-L1 axis.
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http://dx.doi.org/10.1007/s00428-018-02517-1DOI Listing
April 2019

The clinical role of the TME in solid cancer.

Br J Cancer 2019 01 9;120(1):45-53. Epub 2018 Nov 9.

INSERM, UMR_S 1138, Centre de Recherche des Cordeliers, Team "Cancer, immune control and escape", F-75006, Paris, France.

The highly complex and heterogenous ecosystem of a tumour not only contains malignant cells, but also interacting cells from the host such as endothelial cells, stromal fibroblasts, and a variety of immune cells that control tumour growth and invasion. It is well established that anti-tumour immunity is a critical hurdle that must be overcome for tumours to initiate, grow and spread and that anti-tumour immunity can be modulated using current immunotherapies to achieve meaningful anti-tumour clinical responses. Pioneering studies in melanoma, ovarian and colorectal cancer have demonstrated that certain features of the tumour immune microenvironment (TME)-in particular, the degree of tumour infiltration by cytotoxic T cells-can predict a patient's clinical outcome. More recently, studies in renal cell cancer have highlighted the importance of assessing the phenotype of the infiltrating T cells to predict early relapse. Furthermore, intricate interactions with non-immune cellular players such as endothelial cells and fibroblasts modulate the clinical impact of immune cells in the TME. Here, we review the critical components of the TME in solid tumours and how they shape the immune cell contexture, and we summarise numerous studies evaluating its clinical significance from a prognostic and theranostic perspective.
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http://dx.doi.org/10.1038/s41416-018-0327-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6325164PMC
January 2019

Identification and Characterization of Tertiary Lymphoid Structures in Murine Melanoma.

Methods Mol Biol 2018 ;1845:241-257

Beirne B. Carter Center for Immunology Research and Department of Microbiology, Immunology and Cancer Biology, University of Virginia, Charlottesville, VA, USA.

Tertiary lymphoid structures (TLS) are transient ectopic lymphoid aggregates that often share structural similarities to conventional secondary lymphoid organs. In a variety of solid cancers, the presence of these structures commonly correlates with high densities of tumor-infiltrating T lymphocytes and prolonged patient survival. These observations suggest that TLS act as sites for the development of beneficial antitumor immune responses. However, few murine tumor models have been described that could enable a more comprehensive understanding of the functionality of TLS in solid cancers. We previously reported that murine B16-F1 melanoma or Lewis lung carcinoma cells transfected to express the model antigen ovalbumin form intratumoral TLS after implantation into the peritoneal cavity of C57BL/6 mice. In this chapter, we describe immunofluorescent microscopy and flow cytometry approaches for identifying and characterizing intratumoral TLS. Additionally, we describe an adoptive transfer method for demonstrating the infiltration of naïve T cells into B16-OVA melanoma tumors via the lymph node-like vasculature, which is an essential functional feature of tumor-associated TLS.
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http://dx.doi.org/10.1007/978-1-4939-8709-2_14DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6269110PMC
May 2019

Immune Cell Infiltration and Tertiary Lymphoid Structures as Determinants of Antitumor Immunity.

J Immunol 2018 01;200(2):432-442

Carter Immunology Center, University of Virginia School of Medicine, Charlottesville, VA 22908.

Limited representation of intratumoral immune cells is a major barrier to tumor control. However, simply enhancing immune responses in tumor-draining lymph nodes or through adoptive transfer may not overcome the limited ability of tumor vasculature to support effector infiltration. An alternative is to promote a sustained immune response intratumorally. This idea has gained traction with the observation that many tumors are associated with tertiary lymphoid structures (TLS), which organizationally resemble lymph nodes. These peri- and intratumoral structures are usually, but not always, associated with positive prognoses in patients. Preclinical and clinical data support a role for TLS in modulating immunity in the tumor microenvironment. However, there appear to be varied functions of TLS, potentially based on their structure or location in relation to the tumor or the origin or location of the tumor itself. Understanding more about TLS development, composition, and function may offer new therapeutic opportunities to modulate antitumor immunity.
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http://dx.doi.org/10.4049/jimmunol.1701269DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5777336PMC
January 2018

Differential Expression of Homing Receptor Ligands on Tumor-Associated Vasculature that Control CD8 Effector T-cell Entry.

Cancer Immunol Res 2017 12 2;5(12):1062-1073. Epub 2017 Nov 2.

Carter Immunology Center and Department of Microbiology, Immunology, and Cancer Biology, University of Virginia School of Medicine, Charlottesville, Virginia.

Although CD8 T cells are critical for controlling tumors, how they are recruited and home to primary and metastatic lesions is incompletely understood. We characterized the homing receptor (HR) ligands on tumor vasculature to determine what drives their expression and their role in T-cell entry. The anatomic location of B16-OVA tumors affected the expression of E-selectin, MadCAM-1, and VCAM-1, whereas the HR ligands CXCL9 and ICAM-1 were expressed on the vasculature regardless of location. VCAM-1 and CXCL9 expression was induced by IFNγ-secreting adaptive immune cells. VCAM-1 and CXCL9/10 enabled CD8 T-cell effectors expressing αβ integrin and CXCR3 to enter both subcutaneous and peritoneal tumors, whereas E-selectin enabled E-selectin ligand effectors to enter subcutaneous tumors. However, MadCAM-1 did not mediate αβ effector entry into peritoneal tumors due to an unexpected lack of luminal expression. These data establish the relative importance of certain HRs expressed on activated effectors and certain HR ligands expressed on tumor vasculature in the effective immune control of tumors. .
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http://dx.doi.org/10.1158/2326-6066.CIR-17-0190DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6069521PMC
December 2017

Control of CD8 T-Cell Infiltration into Tumors by Vasculature and Microenvironment.

Adv Cancer Res 2015 1;128:263-307. Epub 2015 Jun 1.

Department of Microbiology, Immunology, and Cancer Biology, Carter Immunology Center, University of Virginia School of Medicine, Charlottesville, Virginia, USA. Electronic address:

CD8 T-cells are a critical brake on the initial development of tumors. In established tumors, the presence of CD8 T-cells is correlated with a positive patient prognosis, although immunosuppressive mechanisms limit their effectiveness and they are rarely curative without manipulation. Cancer immunotherapies aim to shift the balance back to dominant antitumor immunity through antibody blockade of immunosuppressive signaling pathways, vaccination, and adoptive transfer of activated or engineered T-cells. These approaches have yielded striking responses in small subsets of patients with solid tumors, most notably those with melanoma. Importantly, the subset of patients who respond to vaccination or immunosuppression blockade therapies are those with CD8 T-cells present in the tumor prior to initiating therapy. While current adoptive cell therapy approaches can be dramatically effective, they require infusion of extremely large numbers of T-cells, but the number that actually infiltrates the tumor is very small. Thus, poor representation of CD8 T-cells in tumors is a fundamental hurdle to successful immunotherapy, over and above the well-established barrier of immunosuppression. In this review, we discuss the factors that determine whether immune cells are present in tumors, with a focus on the representation of cytotoxic CD8 T-cells. We emphasize the critically important role of tumor-associated vasculature as a gateway that enables the active infiltration of both effector and naïve CD8 T-cells that exert antitumor activity. We also discuss strategies to enhance the gateway function and extend the effectiveness of immunotherapies to a broader set of cancer patients.
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http://dx.doi.org/10.1016/bs.acr.2015.05.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4638417PMC
April 2016

Structural and functional features of central nervous system lymphatic vessels.

Nature 2015 Jul 1;523(7560):337-41. Epub 2015 Jun 1.

1] Center for Brain Immunology and Glia, School of Medicine, University of Virginia, Charlottesville, Virginia 22908, USA [2] Department of Neuroscience, School of Medicine, University of Virginia, Charlottesville, Virginia 22908, USA [3] Medical Scientist Training Program, School of Medicine, University of Virginia, Charlottesville, Virginia 22908, USA.

One of the characteristics of the central nervous system is the lack of a classical lymphatic drainage system. Although it is now accepted that the central nervous system undergoes constant immune surveillance that takes place within the meningeal compartment, the mechanisms governing the entrance and exit of immune cells from the central nervous system remain poorly understood. In searching for T-cell gateways into and out of the meninges, we discovered functional lymphatic vessels lining the dural sinuses. These structures express all of the molecular hallmarks of lymphatic endothelial cells, are able to carry both fluid and immune cells from the cerebrospinal fluid, and are connected to the deep cervical lymph nodes. The unique location of these vessels may have impeded their discovery to date, thereby contributing to the long-held concept of the absence of lymphatic vasculature in the central nervous system. The discovery of the central nervous system lymphatic system may call for a reassessment of basic assumptions in neuroimmunology and sheds new light on the aetiology of neuroinflammatory and neurodegenerative diseases associated with immune system dysfunction.
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http://dx.doi.org/10.1038/nature14432DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4506234PMC
July 2015

Effector lymphocyte-induced lymph node-like vasculature enables naive T-cell entry into tumours and enhanced anti-tumour immunity.

Nat Commun 2015 May 13;6:7114. Epub 2015 May 13.

Department of Microbiology and Carter Immunology Center, University of Virginia School of Medicine, Box 801386, Charlottesville, Virginia 22901, USA.

The presence of lymph node (LN)-like vasculature in tumours, characterized by expression of peripheral node addressin and chemokine CCL21, is correlated with T-cell infiltration and positive prognosis in breast cancer and melanoma patients. However, mechanisms controlling the development of LN-like vasculature and how it might contribute to a beneficial outcome for cancer patients are unknown. Here we demonstrate that LN-like vasculature is present in murine models of melanoma and lung carcinoma. It enables infiltration by naive T cells that significantly delay tumour outgrowth after intratumoral activation. Development of this vasculature is controlled by a mechanism involving effector CD8 T cells and NK cells that secrete LTα3 and IFNγ. LN-like vasculature is also associated with organized aggregates of B lymphocytes and gp38(+) fibroblasts, which resemble tertiary lymphoid organs that develop in models of chronic inflammation. These results establish LN-like vasculature as both a consequence of and key contributor to anti-tumour immunity.
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http://dx.doi.org/10.1038/ncomms8114DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4435831PMC
May 2015

Roles of lymphatic endothelial cells expressing peripheral tissue antigens in CD4 T-cell tolerance induction.

Nat Commun 2015 Apr 10;6:6771. Epub 2015 Apr 10.

Carter Immunology Center, Department of Microbiology, Immunology and Cancer Biology, University of Virginia School of Medicine, Charlottesville, Virginia 22908, USA.

Lymphatic endothelial cells (LECs) directly express peripheral tissue antigens and induce CD8 T-cell deletional tolerance. LECs express MHC-II molecules, suggesting they might also tolerize CD4 T cells. We demonstrate that when β-galactosidase (β-gal) is expressed in LECs, β-gal-specific CD8 T cells undergo deletion via the PD-1/PD-L1 and LAG-3/MHC-II pathways. In contrast, LECs do not present endogenous β-gal in the context of MHC-II molecules to β-gal-specific CD4 T cells. Lack of presentation is independent of antigen localization, as membrane-bound haemagglutinin and I-Eα are also not presented by MHC-II molecules. LECs express invariant chain and cathepsin L, but not H2-M, suggesting that they cannot load endogenous antigenic peptides onto MHC-II molecules. Importantly, LECs transfer β-gal to dendritic cells, which subsequently present it to induce CD4 T-cell anergy. Therefore, LECs serve as an antigen reservoir for CD4 T-cell tolerance, and MHC-II molecules on LECs are used to induce CD8 T-cell tolerance via LAG-3.
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http://dx.doi.org/10.1038/ncomms7771DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4403767PMC
April 2015

Peripheral tissue homing receptor control of naïve, effector, and memory CD8 T cell localization in lymphoid and non-lymphoid tissues.

Front Immunol 2013 19;4:241. Epub 2013 Aug 19.

Department of Microbiology, Immunology, and Cancer Biology, Carter Immunology Center, University of Virginia School of Medicine , Charlottesville, VA , USA.

T cell activation induces homing receptors that bind ligands on peripheral tissue vasculature, programing movement to sites of infection and injury. There are three major types of CD8 effector T cells based on homing receptor expression, which arise in distinct lymphoid organs. Recent publications indicate that naïve, effector, and memory T cell migration is more complex than once thought; while many effectors enter peripheral tissues, some re-enter lymph nodes (LN), and contain central memory precursors. LN re-entry can depend on CD62L or peripheral tissue homing receptors. Memory T cells in LN tend to express the same homing receptors as their forebears, but often are CD62Lneg. Homing receptors also control CD8 T cell tumor entry. Tumor vasculature has low levels of many peripheral tissue homing receptor ligands, but portions of it resemble high endothelial venules (HEV), enabling naïve T cell entry, activation, and subsequent effector activity. This vasculature is associated with positive prognoses in humans, suggesting it may sustain ongoing anti-tumor responses. These findings reveal new roles for homing receptors expressed by naïve, effector, and memory CD8 T cells in controlling entry into lymphoid and non-lymphoid tissues.
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http://dx.doi.org/10.3389/fimmu.2013.00241DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3746678PMC
August 2013