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Inhibitory Mechanisms in the TME investigators

Greg Delgoffe, PhD
Contact:
Hillman Cancer Center, Suite 2.26e
5115 Centre Ave
Pittsburgh PA
Phone: 412-623-4658
Research Interests and Keywords:
  • Tumor immunology
  • regulatory T cells
  • immunometabolism
  • cancer immunotherapy
Summary

In recent years, the decades-long promise of tumor immunotherapy has finally begun to come to fruition. Checkpoint blockade, for example, represents a critically important intervention for potentiating the antitumor immune response. In these therapies, blockade of T cell intrinsic negative regulators (such as CTLA-4 and PD-1 signaling) releases the brake on effector T cells in the tumor, resulting in substantial, durable antitumor immunity, and clinical responses.

While negative regulators on the effector T cells can be relieved through these interventions, effector T cells still face a variety of cell extrinsic modes of immune suppression, notably through suppression via regulatory T (Treg) cells. Treg cells play critical roles in preventing autoimmune responses to self tissues as well as limiting immunopathology during exuberant immune responses. However, Treg cells represent a major barrier to antitumor immunity. Many tumors recruit, activate, and expand large numbers of Treg cells, which can be specific for any number of normal, self antigens expressed by the tumor. While depletion of total Treg cells can result in autoimmune pathologies, inhibition of Treg cell stability or function has been shown to allow for local inhibition of Treg cell suppression in the tumor, while sparing normal tissues from an autoimmune response.

Thus, finding phenotypic, signaling, or functional parameters that distinguish intratumoral Treg and conventional T (Tconv) cells could shed light on mechanisms by which Treg cells could be targeted to allow for a greater antitumor response. Recent studies have found that Tconv and Treg cells have distinct metabolic requirements. Not unlike cancer cells, conventional T cells undergo aerobic glycolysis (the 'Warburg effect') when undergoing robust expansion. However, regulatory T cells utilize alternative sources of fuel. Our initial findings in the laboratory suggest that not only do intratumoral Treg cells utilize distinct fuel from their conventional brethren, but engage different metabolic pathways from Treg cells in normal tissues and lymphoid organs. This suggests that metabolic pathways, or their downstream targets, could be targeted in order to inhibit intratumoral Treg cells specifically, releasing a crucial cell extrinsic brake on the antitumor immune response. The goal is to provide alternative modalities of therapy that could be utilized alone or in combination with other immunotherapeutic strategies, to allow for robust and durable immune responses for the eradication of cancer.

Robert Ferris, MD, PhD
Contact:
UPMC Hillman Cancer Center
Cancer Pavilion, Suite 500 5150 Centre Ave.
Pittsburgh PA
Research Interests and Keywords:
  • Antigen presentation
  • cancer vaccines
  • CXC chemokines
  • immunotherapy
  • squamous cell carcinoma
  • head and neck cancer
  • tumor microenvironment
  • viruses and cancer
  • HPV
Summary

Dr. Ferris's laboratory is focused on understanding basic immunological mechanisms of the T lymphocyte response to cancer, for the development of novel immunotherapeutic approaches to head and neck cancers (HNC). Tumor vaccine clinical trials are currently underway and new strategies are in development. We are particularly interested in the immune response to human papillomavirus (HPV)-associated head and neck cancer, which appears to be a distinct subgroup of head and neck squamous cell carcinomas. Monitoring the successful immune effects of individuals treated with immunotherapy is a major effort, in order to develop improved generations of vaccine approaches. We are also studying tumor induced immune evasion, such as defective antigen processing and presentation to subvert cytotoxic T lymphocyte recognition of tumors.

Another area of study involves the promotion of tumor metastasis by a family of molecules called chemokines. We are finding important roles for chemokine receptors in cancer metastasis. These chemokines are small, secreted molecules that mediate homing and recruitment of immune cells in response to inflammation, through a family of G-protein linked receptors. Overall, these studies are designed to identify the chemokines relevant to progression of HNC and to provide initial data on their possible clinical utility as components of future vaccination therapies for HNC. In addition, our group is interested in developing immune/inflammatory biomarkers present in the bloodstream for HNC detection, and monitoring in populations at risk for cancer recurrence and/or second primary tumors.

Dario Vignali, PhD
Contact:
99999
Pittsburgh PA
Research Interests and Keywords:
  • Regulatory T cells
  • tumor immunology
  • cytokine signaling
Albert Donnenberg, PhD
Contact:
450 Technology Drive
Suite 300
Pittsburgh PA
Research Interests and Keywords:
  • Hematopoietic stem cell transplantation
  • bone marrow- and peripheral blood-derived stem and progenitor cells for regenerative therapy
  • cancer stem-cell hypothesis
  • technological advances in flow cytometry
Lawrence Kane, PhD
Contact:
E-1054 BSTWR
200 Lothrop St.
Pittsburgh PA
Phone: 412-383-6880
Research Interests and Keywords:
  • T cells
  • signal transduction
  • kinases
  • immunology
  • mast cells
  • co-stimulation
Summary
My lab is focused on the study of signal transduction pathways that regulate antigen-dependent activation of T cells and mast cells. Toward that end, we are engaged in several specific projects: 1. Understanding the signaling pathways downstream of Carma1, MALT1 and Bcl10 (CBM complex) in T cells 2. Defining biochemical and spatial regulation of NF-kB activation by the TCR/CD3 complex, along with CD28 co-stimulation 3. Understanding signal transduction pathways downstream of the transmembrane proteins Tim-1 and Tim-3, in T cells and mast cells
Michael Shurin, MD, PhD
Contact:
S735, Scaife Hall
3550 Terrace Street
Pittsburgh PA
Phone: 412-648-9831
Research Interests and Keywords:
  • Tumor-induced immunomodulation
  • dendritic cells
  • cancer immunotherapy
  • psychoneuroendocrine factors of immunosuppression in cancer
Hassane Zarour, MD
Contact:
Hillman Cancer Center, Research Pavilion
5117 Centre Avenue Lab 1.32a
Pittsburgh PA
Phone: 412-623-3244
Research Interests and Keywords:
  • Cancer immunology
  • cancer immunotherapy
  • melanoma
  • skin cancer
Summary
Hassane Zarour, MD is a dermatologist and cancer immunologist whose research focuses on basic and translational human cancer immunology in the melanoma field. His work has led to the identification of novel melanoma MHC class II-presented epitopes that have been used in investigator-initiated trials at UPMC Hillman Cancer Center as well as in multi-center trials. Most recently, Dr. Zarour's work has contributed to elucidating the role of inhibitory receptors in promoting melanoma-induced T cell dysfunction in the tumor microenvironment. These findings led to the development of novel antibodies targeting inhibitory receptors for clinical trials. Dr. Zarour actively contributes to the design and the implementation of novel investigator-initiated trials based on laboratory findings, including two melanoma vaccine trials funded by the Cancer Research Institute and the National Cancer Institute, respectively. He is the lead scientific investigator on the Hillman Skin Cancer SPORE Project 3 that is testing the novel combination of BRAF inhibitor (BRAFi) therapy with high-dose interferon for metastatic V600E positive melanoma. He is also testing a novel combination of an anti-PD-1 antibody (MK 3475/Pembrolizumab) and PEG-interferon with grant support from an academic-industry award of the Melanoma Research Alliance.
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