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Stimulatory Mechanisms in the TME investigators

Robert Binder, PhD
Contact:
E1051 BSTWR
200 Lothrop St.
Pittsburgh PA
Research Interests and Keywords:
  • Antigen cross-presentation
  • tumor immunology
  • immunotherapy
  • heat shock proteins
  • cancer vaccines
Summary

Our research interests are focused on the mechanisms of cross-priming of antigens during immune responses to cancer, viruses and autoimmunity. The pursuit of this research area stems from the observations that in many situations, heat shock proteins (HSPs) are both necessary and sufficient for cross-presentation. HSPs are adept at this because of several unique properties, including their ability to:

  1. chaperone peptides;
  2. bind to HSP receptors (CD91) for endocytosis; and
  3. stimulate immune cells to up-regulate costimulation.

HSPs thus elicit remarkable immune responses specific for the peptides they chaperone. The laboratory is using these observations to examine new facets of antigen presentation and also to develop novel immunotherapies for cancer, infectious disease and autoimmune disorders.

A related area of research examines how other ligands for the HSP receptor CD91 interact with the immune system. In the past few years, we have shown that a2-macroglobulin (a2M), a CD91 ligand, though not a bonafide HSP, shares the immunogenic properties of HSPs and can elicit immune responses specific to (peptide) substrates that it chaperones. We are currently exploring the identification of naturally formed a2M-substrate complexes and the potential use of these immunogenic complexes as therapeutic agents for cancer and infectious disease.

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.

Yi-Nan Gong
Binfeng Lu, PhD
Contact:
E1047 BST
Pittsburgh PA
Research Interests and Keywords:
  • Tumor immunology
Mark Shlomchik, MD, PhD
Contact:
200 Lothrop St
E1040 BSTWR
Pittsburgh PA
Research Interests and Keywords:
  • B cell development
  • immunopathogenesis
Walter Storkus, PhD
Contact:
W1041.2 BST
Pittsburgh PA
Phone: 412-383-8643
Research Interests and Keywords:
  • Tumor biology
  • cancer vaccines
  • immunotherapy
  • gene therapy
  • dendritic cells
  • melanoma
  • renal cell carcinoma
Summary
Our laboratory research focuses on the study of tumor immunobiology and designing immunotherapies for the treatment of cancer. Our translational murine models and human in vitro studies are intended to serve as a foundation for the development of phase I/II clinical trials of modalities that can more effectively treat patients with melanoma or renal cell carcinoma. Such modalities include dendritic cell (DC)-based vaccines, cytokine gene-modified DC injected directly into tumor lesions, and combinational approaches integrating agents that modulate tumor cell immune recognition (i.e., HSP90 inhibitors) or alter the balance of Type-1 versus regulatory immunity in the tumor microenvironment (i.e., sunitinib). Most recently, we have discovered that immune targeting of the tumor-associated vasculature occurs naturally as a consequence of effective immunotherapy (via DC1-based cross-priming of T cells), and that vaccines based on tumor-associated blood antigens (TBVA) can promote tumor regression even in cases where cancer cells cannot be directly recognized by the protective CD8+ immune system. We have also determined that anti-angiogenic agents such as the tyrosine kinase inhibitors sunitinib, axitinib and dasatinib all lead to tumor vascular normalization and to the improved delivery of anti-TBVA T cells into the tumor microenvironment (TME) allowing for improved anti-tumor efficacy. This has most recently resulted in the development of our NIH-supported clinical trial UPCI 12-048 'A Randomized Phase II Pilot Study of Type I-Polarized Autologous Dendritic Cell Vaccines Incorporating Tumor Blood Vessel Antigen (TBVA)-Derived Peptides in Combination with Dasatinib in Patients with Metastatic Melanoma' (H. Tawbi, Clinical PI) that is currently accruing patients.
Anda Vlad, MD, PhD
Contact:
204 Craft Avenue, B403
Pittsburgh PA
Phone: 412-641-2985
Research Interests and Keywords:
  • Ovarian cancer
  • immunology
  • immune surveillance
  • biomarkers
  • endometriosis
Summary
Proposing to identify immune biomarker discovery for disease management of endometriosis and ovarian cancer, the Vlad lab is investigating numerous questions about immune surveillance in women with these diseases. Via collaborations with our clinician colleagues at Magee-Womens Hospital of UPMC, the lab is working on implementing new clinical trials exploring the roles of novel immune biologics as adjuvant therapies in ovarian cancer.
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.

Olivera Finn, PhD
Contact:
E1044 BST (Office)
Pittsburgh PA
Research Interests and Keywords:
  • Cancer vaccines
  • tumor-specific immunity
Saumendra Sarkar, PhD
Contact:
Hillman Cancer Center
Lab 1.7 5117 Centre Avenue
Pittsburgh PA
Research Interests and Keywords:
  • RIG-I-like receptors (RLR)
  • interferon (IFN)-stimulated genes
  • toll-like receptor 3 (TLR3)
  • innate immune signaling
  • anti-viral innate immunity
  • type I IFN; IFN signaling
  • IFN regulatory factor 3 (IRF3)
  • tumor microenvironment
Summary
Innate immunity of an organism is the inborn protection against invading pathogens. Because it is inborn, and entrusted with the protection of the host from a vast array of previously unknown invaders, the innate immune system generates a generalized alert response upon pathogen detection. This alert is chemically mediated by a class of molecules called cytokines, such as interferons. A critical task for this host protection system is to distinguish foreign or non-self, from self, and initiate their destruction or containment. The sensors or the receptors of the innate immune system accomplish this by recognizing specific molecular patterns, which are common to pathogens or pathogen associated molecules, but absent in the host. We focus on a particular subset of these sensors/receptors, which are involved in sensing virus infection. In order to protect the host from viral invasion, the innate immune system has evolved sensors to detect foreign nucleic acids. Several unique features of virally produced DNA or RNA are exploited to distinguish viral nucleic acids from that of the host. One such unique nucleic acid is double-stranded RNA (dsRNA) ' a common byproduct or intermediate in viral genome replication. In mammals, receptors like toll-like receptor 3 (TLR3), retinoic acid-inducible gene I (RIG-I), and melanoma differentiation-associated gene 5 (MDA5) are the three known sensors of dsRNA. Single-stranded viral RNA is sensed by toll-like receptors 7 and 8 (TLR7 and TLR8), while viral DNA is detected by toll-like receptor 9 (TLR9) and other cytoplasmic receptors. We study two related aspects of the signaling process involved in interferon production in the context of infectious disease and cancer: 1) modulation of viral RNA sensing mechanisms; and 2) alternative mechanisms of interferon induction in specific tumors.
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
Dario Vignali, PhD
Contact:
99999
Pittsburgh PA
Research Interests and Keywords:
  • Regulatory T cells
  • tumor immunology
  • cytokine signaling
Theresa Whiteside, PhD
Contact:
Hillman Cancer Center
1.27d
Pittsburgh PA
Research Interests and Keywords:
  • Tumor immunology
  • cancer immunotherapy
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