Research

Research Programs

Immunology and Immunotherapy

Program Members | Research Highlights | Contacts

The immune system is closely intertwined with both cancer pathogenesis and treatment.  On the one hand, cancer is a manifestation of failures in immunity.  Cancer cells that express mutant proteins manage to escape detection and elimination by the immune system.  Chronic infections that persist due to incompletely effective immune responses also contribute to cancer. Some, such as human papillomavirus (HPV) and Epstein-Barr virus (EBV) are directly oncogenic, while others such as H. pylori, hepatitis C virus, hepatitis B virus and Chlamydia psittaci promote cancers by inducing chronic but ineffective immune stimulation.  Similarly, chronic autoimmunity is linked to lymphoid malignancies or, in the case of inflammatory bowel disease, to colon carcinoma.  Machinery that evolved for the generation of antigen receptor diversity on immune cells is co-opted in oncogenesis.  On the other hand, the potency and specificity of the immune system can be a powerful tool that eliminates neoplastic cells.  The success of the antibody Rituxan in treating CD20+ lymphomas and allogeneic stem cell transplantation (alloSCT) in treating hematopoietic malignancies highlight the potential of both antibody and T cell-based therapies.  Nevertheless, immunotherapy of cancer is clearly in its infancy and recent and ongoing advances in basic immunology only now make it possible to more rationally explore the potential of the adaptive immune system to treat cancer.

With this background in mind, the goals of the Immunology and Immunotherapy Program are to:

1. To elucidate the fundamental nature of molecular and cellular mechanisms of immunity. 
   Basic research in immunology is conducted in four thematic areas: a) antigen presentation, b) T cell responses and their regulation, c) innate immunity and the links between the innate and adaptive immune system, and d) B cell function and cell biology.  Seminal discoveries made at Yale in the fields of antigen processing, antigen cross-presentation, Toll-like receptor (TLR) function and mechanisms of T cell regulation and polarization have already begun to influence studies in the clinic.
2. To encourage research in human cancer immunology.
   The Immunology & Immunotherapy Program has a core group of investigators that use mice to investigate cancer immunity in models of allogeneic stem cell transplantation, melanoma, breast cancer, HPV infection and cutaneous malignancy.  This work is strongly supported by the outstanding immunology research in non-cancer specific models.  Since communication between these two groups is essential to achieve this end, a major goal is to sure that such interactions remain effective and robust.
3. To develop and implement novel investigator-initiated trials in cancer immunotherapy. 
   The Immunology & Immunotherapy Program already has ongoing programs and therapeutic trials in allogeneic stem cell transplantation, extracorporeal photopheresis, melanoma immunotherapy, and vaccine development.

Program Members
Warren Shlomchik, MD, Program Director; Associate Professor of Internal Medicine (Medical Oncology) & Immunobiology

Francine Foss, MD, Program Co-Director; Professor of Internal Medicine (Medical Oncology)

Michael Girardi, MD, Program Co-Director; Associate Professor of Dermatology

Stephan Ariyan, MD, Clinical Professor of Surgery

Philip Askenase, MD, Professor of Medicine and Pathology

Jeffrey Bender, MD, Robert R. Levy Professor of Preventive Cardiology; Professor of Medicine and Immunobiology

Carol Berger, PhD, Research Scientist, Department of Dermatology

Alfred Bothwell, PhD, Professor of Immunobiology, and Interdepartmental Program in Vascular Biology and Transplantation

Dennis Cooper, MD, Professor of Internal Medicine; Director, Stem Cell Transplant Program

Joseph Craft, PhD, Professor of Medicine and Immunobiology

Peter Cresswell, PhD, Professor of Immunobiology, Cell Biology, and Dermatology

Richard Edelson, MD, Professor and Chairman of Dermatology

Jack Elias, MD, Chairman of Internal Medicine; Waldemar Von Zedtwitz Professor of Medicine

Richard Flavell, PhD, Sterling Professor and Chairman of Immunobiology; Professor of Molecular, Cellular and Developmental Biology

Jorge Galán, PhD, Lucille P. Markey Professor and Chairman of Microbial Pathogenesis; Professor of Cell Biology

Sankar Ghosh, PhD, Professor of Immunobiology and Molecular Biophysics & Biochemistry

Earl Glusac, MD, Professor of Pathology and Dermatolog

Daniel Goldstein, MD, Assistant Professor of Medicine

Douglas Hanlon, PhD, Associate Research Scientist, Department of Dermatology

Peter Heald, MD, Professor of Dermatology

Mark Horowitz, PhD, Professor of Orthopaedics and Rehabilitation

Karl Insogna, MD, Professor of Internal Medicine; Director, Yale Bone Center

Paula Kavathas, PhD, Professor of Laboratory Medicine, Genetics, and Immunobiology

Harriet Kluger, MD, Associate Professor of Medical Oncology

Martin Kluger, PhD, Research Scientist, Department of Dermatology

Diane Krause, MD, PhD, Professor of Laboratory Medicine and Cell Biology

Mark Mamula, PhD, Associate Professor of Medicine

Jennifer McNiff, MD, Professor of Dermatology and Pathology

Ruslan Medzhitov, PhD, Professor of Immunobiology

Kenneth Miller, MD, Assistant Professor of Internal Medicine (Medical Oncology)

Deepak Narayan, MD, Associate Professor of Surgery

Jordan Pober, MD, PhD, Professor and Vice Chairman of Immunobiology; Professor of Dermatology and Pathology

David Rothstein, MD, Associate Professor of Medicine

Nancy Ruddle, PhD, Professor of Epidemiology & Public Health and Immunobiology

David Schatz, PhD, Professor of Immunobiology

Mark Shlomchik, MD, PhD, Professor of Laboratory Medicine and Immunobiology

Stuart Seropian, MD, Associate Professor of Internal Medicine (Medical Oncology)

Brian Smith, MD, Professor and Chairman of Laboratory Medicine; Professor of Internal Medicine and Pediatrics

Edward Snyder, MD, Professor of Laboratory Medicine

Robert Tigelaar, MD, Professor of Dermatology and Immunobiology

Agnes Vignery, PhD, Associate Professor of Orthopaedics & Rehabilitation and   Molecular Cellular Biology

Research Highlights

• The discovery of mammalian Toll-Like Receptors (TLRs) which are pivotal links between innate recognition of pathogens and the stimulation of adaptive immune responses. Led by the pioneering discoveries by Ruslan Medzhitov, Immunology & Immunotherapy Program members (including Drs. Flavell, Ghosh, M. Shlomchik, W. Shlomchik, and Goldstein) are perhaps the most productive group worldwide in studying TLRs as they relate to infection, autoimmunity, cancer immunotherapy and transplantation. Drs. Medzhitov, Flavell and Ghosh are also leaders in understanding the signaling pathways downstream of TLRs that influence gene expression and immune responses.  These discoveries will no doubt contribute to strategies to control chronic infections linked to cancer and to harness the immune system to eliminate neoplastic cells.

• Immunology & Immunotherapy Program investigators have made important discoveries directly related to cancer. Michael Girardi has made important discoveries into how cutaneous inflammation promotes cancer, and in particular how gδT cells contribute to this process. Richard Flavell’s lab has discovered how blockade of TGF-b augments anti-tumor responses mediated by both T cells and natural killer cells. Warren Shlomchik has dissected the molecular and cellular mechanisms whereby donor T cells in allogeneic stem cell transplantation kill leukemia cells. Further, in collaboration with Mark Shlomchik, they have discovered that subsets of memory T cells can be safely transferred without attacking the transplant recipient but can still mediate anti-cancer effects. Warren Shlomchik is translating this discovery into the clinic. 

• Richard Flavell is the foremost investigator in applying genetic approaches in dissecting molecular and cellular immune pathways. His recent contributions are numerous and include understanding the regulation of programmed cell death, cytokine gene expression, TLR function and signaling, and innate inflammation. He is also leading the effort to create a “humanized” mouse that can support the development and function of human immune cells. He is inserting into mice human genes for hematopoietic growth factors, chemokines, integrins and major histocompatibility complex antigens (amongst others). These mice will be an invaluable resource for studying lymphomas and how to initiate adaptive and innate immune responses with human cells in an in vivo system.

• Peter Cresswell has made enormous contributions into how antigen is presented by specialized antigen-presenting cells to T cells. This work is also essential for vaccination strategies against cancer.

• Mark Shlomchik’s lab has been using intravital imaging to understand germinal center B cell responses. This understanding should be pivotal in advancing our knowledge of how and when B cell malignant transformation occurs as most B cell malignancies are categorized in reference to the germinal center.

Contacts
Warren Shlomchik, MD, Program Director
(203) 737-2478
warren.shlomchik@yale.edu

Francine Foss, MD, Program Co-Director
(203) 737-5312
francine.foss@yale.edu

Michael Girardi, MD, Program Co-Director
(203) 785-4092
michael.girardi@yale.edu