Pamela Ohashi

Last updated
Pamela Ohashi
Alma materUniversity of Toronto
AwardsRobert L Noble Prize 2018
Hardy Cinader Award 2014
Scientific career
FieldsCancer Immunotherapy
InstitutionsUniversity of Toronto
Princess Margaret Hospital
Thesis Molecular analysis and expression of T cell antigen receptor genes
Doctoral advisor Tak Wah Mak

Pamela Sumiko Ohashi, PhD, FRSC is a Canadian medical researcher. She is co-director of the Campbell Family Institute for Breast Cancer Research, director of the Cancer Immune Therapy Program at the Princess Margaret Cancer Centre and a professor at the University of Toronto.

Contents

Education

Ohashi obtained her BSc in biology from York University in 1982. [1]

She received her PhD from the University of Toronto Department of Immunology in 1988. Her graduate supervisor was Tak Wah Mak. [1] [2]

Scientific career

In her undergraduate studies at York University, Ohashi did wet lab research in the laboratories of James Friesen, John Heddle, and Ron Pearlman. [1]

Following an interest in immunology, she pursued a PhD in Tak Mak’s lab at Princess Margaret Hospital, graduating in 1988. [1] [2]

Ohashi conducted post-doctoral research with Rolf Zinkernagel and Hans Hengartner at the University of Zurich until 1991. [1] [2] [3]

In 1992, Ohashi established a research program at Princess Margaret Hospital, where she is now a Senior Scientist. [4]

Ohashi is a Professor in the Departments of Medical Biophysics and Immunology at the University of Toronto. [3] [5]

At Princess Margaret Cancer Centre, Ohashi is Co-Director of the Campbell Family Institute for Breast Cancer Research, and Director of the Cancer Immune Therapy Program.

Her achievements resulted in her appointment as Canada Research Chair in Autoimmunity and Tumour Immunity. [6]

Research

Ohashi undertook a fourth year undergraduate research project with Dr Ron Pearlman on genomic analysis of Tetrahymena repetitive sequences. [1] [7]

In her PhD research on T Cell Receptors (TCR), Ohashi found that expression of beta chain cDNA was essential for the expression of a functional TCR/CD3 complex on the cell surface. This complex was shown to be responsible for mediating signal transduction via specific stimulation of the TCR of Jurkat cells. [8] She created mouse lines with transgenic T cells expressing rearranged TCR genes and showed evidence supporting the model that commitment to certain T cell lineages occurs prior to the rearrangement of the composite receptor genes. [9]

Ohashi’s early work focused on understanding basic mechanisms of T cell tolerance versus activation. She was a pioneer in showing conclusively that thymocyte selection is based on an affinity/avidity model. [2] [10] [11] She was also the first to demonstrate that self-reactive peripheral T cells can remain in a naïve state in the T cell repertoire; a concept that has become widely known as T cell “ignorance”. [2] [12]  

This has led to Ohashi’s current approach in understanding how to manipulate and improve cytotoxic T cells to enhance the immune response against cancer. [1] She demonstrated that ignorant T cells could be activated against tumours and showed that altering the molecular programming of dendritic cells can alter the steady state and promote T cell activation in the absence of conventional dendritic cell maturation signals. [2] [13] [14] [15] This is a novel way to break T cell tolerance in vivo and provides important insights into potential mechanisms of autoimmunity. [2] [16]

Ohashi directs the translational program of Princess Margaret Cancer Centre's Cancer Immune Therapy Program, designing and running clinical trials using novel immune therapeutic approaches to treat cancer patients. [4] Ohashi was a key investigator on the first Phase I clinical trial to use adoptive cell therapy for ovarian cancer. [17]

Awards and distinctions

2018: Robert L Noble Prize [3] [18]

2015: Member of the Board of Directors of the Society for Immunotherapy of Cancer [3] [19]

2014: Hardy Cinader Award [2]

2011: CSI Investigator Award [20]

2006: Fellow of the Royal Society of Canada [21]

2003: Pharmingen Investigator Award [22]

1998: William E. Rawls Award [1] [2]

Chair of the AACR Immunotherapy Steering committee [3]

Founding Senior Editor: Cancer Immunology Research [3]

Related Research Articles

<span class="mw-page-title-main">Antigen</span> Molecule triggering an immune response (antibody production) in the host

In immunology, an antigen (Ag) is a molecule, moiety, foreign particulate matter, or an allergen, such as pollen, that can bind to a specific antibody or T-cell receptor. The presence of antigens in the body may trigger an immune response.

<span class="mw-page-title-main">Dendritic cell</span> Accessory cell of the mammalian immune system

A dendritic cell (DC) is an antigen-presenting cell of the mammalian immune system. A DC's main function is to process antigen material and present it on the cell surface to the T cells of the immune system. They act as messengers between the innate and adaptive immune systems.

Immunotherapy or biological therapy is the treatment of disease by activating or suppressing the immune system. Immunotherapies designed to elicit or amplify an immune response are classified as activation immunotherapies, while immunotherapies that reduce or suppress are classified as suppression immunotherapies. Immunotherapy is under preliminary research for its potential to treat various forms of cancer.

<span class="mw-page-title-main">Cancer immunotherapy</span> Artificial stimulation of the immune system to treat cancer

Cancer immunotherapy (immuno-oncotherapy) is the stimulation of the immune system to treat cancer, improving the immune system's natural ability to fight the disease. It is an application of the fundamental research of cancer immunology and a growing subspecialty of oncology.

<span class="mw-page-title-main">Antigen-presenting cell</span> Cell that displays antigen bound by MHC proteins on its surface

An antigen-presenting cell (APC) or accessory cell is a cell that displays an antigen bound by major histocompatibility complex (MHC) proteins on its surface; this process is known as antigen presentation. T cells may recognize these complexes using their T cell receptors (TCRs). APCs process antigens and present them to T cells.

Cross-presentation is the ability of certain professional antigen-presenting cells (mostly dendritic cells) to take up, process and present extracellular antigens with MHC class I molecules to CD8 T cells (cytotoxic T cells). Cross-priming, the result of this process, describes the stimulation of naive cytotoxic CD8+ T cells into activated cytotoxic CD8+ T cells. This process is necessary for immunity against most tumors and against viruses that infect dendritic cells and sabotage their presentation of virus antigens. Cross presentation is also required for the induction of cytotoxic immunity by vaccination with protein antigens, for example, tumour vaccination.

Tak Wah Mak, is a Canadian medical researcher, geneticist, oncologist, and biochemist. He first became widely known for his discovery of the T-cell receptor in 1983 and pioneering work in the genetics of immunology. In 1995, Mak published a landmark paper on the discovery of the function of the immune checkpoint protein CTLA-4, thus opening the path for immunotherapy/checkpoint inhibitors as a means of cancer treatment. Mak is also the founder of Agios Pharmaceuticals, whose lead compound, IDHIFA®, was approved by the FDA for acute myeloid leukemia in August 2017, becoming the first drug specifically targeting cancer metabolism to be used for cancer treatment. He has worked in a variety of areas including biochemistry, immunology, and cancer genetics.

<span class="mw-page-title-main">CD40 (protein)</span> Mammalian protein found in humans

Cluster of differentiation 40, CD40 is a type I transmembrane protein found on antigen-presenting cells and is required for their activation. The binding of CD154 (CD40L) on TH cells to CD40 activates antigen presenting cells and induces a variety of downstream effects.

Co-stimulation is a secondary signal which immune cells rely on to activate an immune response in the presence of an antigen-presenting cell. In the case of T cells, two stimuli are required to fully activate their immune response. During the activation of lymphocytes, co-stimulation is often crucial to the development of an effective immune response. Co-stimulation is required in addition to the antigen-specific signal from their antigen receptors.

<span class="mw-page-title-main">CD80</span> Mammalian protein found in Homo sapiens

The Cluster of differentiation 80 is a B7, type I membrane protein in the immunoglobulin superfamily, with an extracellular immunoglobulin constant-like domain and a variable-like domain required for receptor binding. It is closely related to CD86, another B7 protein (B7-2), and often works in tandem. Both CD80 and CD86 interact with costimulatory receptors CD28, CTLA-4 (CD152) and the p75 neurotrophin receptor.

<span class="mw-page-title-main">CD86</span> Mammalian protein found in Homo sapiens

Cluster of Differentiation 86 is a protein constitutively expressed on dendritic cells, Langerhans cells, macrophages, B-cells, and on other antigen-presenting cells. Along with CD80, CD86 provides costimulatory signals necessary for T cell activation and survival. Depending on the ligand bound, CD86 can signal for self-regulation and cell-cell association, or for attenuation of regulation and cell-cell disassociation.

<span class="mw-page-title-main">Cancer immunology</span> Study of the role of the immune system in cancer

Cancer immunology (immuno-oncology) is an interdisciplinary branch of biology and a sub-discipline of immunology that is concerned with understanding the role of the immune system in the progression and development of cancer; the most well known application is cancer immunotherapy, which utilises the immune system as a treatment for cancer. Cancer immunosurveillance and immunoediting are based on protection against development of tumors in animal systems and (ii) identification of targets for immune recognition of human cancer.

Gamma delta T cells are T cells that have a γδ T-cell receptor (TCR) on their surface. Most T cells are αβ T cells with TCR composed of two glycoprotein chains called α (alpha) and β (beta) TCR chains. In contrast, γδ T cells have a TCR that is made up of one γ (gamma) chain and one δ (delta) chain. This group of T cells is usually less common than αβ T cells. Their highest abundance is in the gut mucosa, within a population of lymphocytes known as intraepithelial lymphocytes (IELs).

<span class="mw-page-title-main">Lymphocyte-activation gene 3</span>

Lymphocyte-activation gene 3, also known as LAG-3, is a protein which in humans is encoded by the LAG3 gene. LAG3, which was discovered in 1990 and was designated CD223 after the Seventh Human Leucocyte Differentiation Antigen Workshop in 2000, is a cell surface molecule with diverse biological effects on T cell function but overall has an immune inhibitory effect. It is an immune checkpoint receptor and as such is the target of various drug development programs by pharmaceutical companies seeking to develop new treatments for cancer and autoimmune disorders. In soluble form it is also being developed as a cancer drug in its own right.

T helper 3 cells (Th3) are a subset of T lymphocytes with immunoregulary and immunosuppressive functions, that can be induced by administration of foreign oral antigen. Th3 cells act mainly through the secretion of anti-inflammatory cytokine transforming growth factor beta (TGF-β). Th3 have been described both in mice and human as CD4+FOXP3− regulatory T cells. Th3 cells were first described in research focusing on oral tolerance in the experimental autoimmune encephalitis (EAE) mouse model and later described as CD4+CD25−FOXP3−LAP+ cells, that can be induced in the gut by oral antigen through T cell receptor (TCR) signalling.

<span class="mw-page-title-main">Centre d'immunologie de Marseille-Luminy</span>

The Centre d’Immunologie de Marseille-Luminy (CIML) was founded in 1976 and has been described by AERES, an independent evaluation agency, as "without doubt one of the best immunology centers of excellence in Europe". The CIML addresses all areas of contemporary immunology; it is located in Marseille in the South of France.

Natural killer T (NKT) cells are a heterogeneous group of T cells that share properties of both T cells and natural killer cells. Many of these cells recognize the non-polymorphic CD1d molecule, an antigen-presenting molecule that binds self and foreign lipids and glycolipids. They constitute only approximately 1% of all peripheral blood T cells. Natural killer T cells should neither be confused with natural killer cells nor killer T cells.

<span class="mw-page-title-main">Immune checkpoint</span> Regulators of the immune system

Immune checkpoints are regulators of the immune system. These pathways are crucial for self-tolerance, which prevents the immune system from attacking cells indiscriminately. However, some cancers can protect themselves from attack by stimulating immune checkpoint targets.

<span class="mw-page-title-main">Mark M. Davis</span> American immunologist (born 1952)

Mark Morris Davis is an American immunologist. He is the director of and Avery Family Professor of Immunology at the Institute for Immunity, Transplantation and Infection at Stanford University.

The dendritic cell-based cancer vaccine is an innovation in therapeutic strategy for cancer patients.

References

  1. 1 2 3 4 5 6 7 8 "Alumni Spotlight - Pamela Ohashi". York University.
  2. 1 2 3 4 5 6 7 8 9 "Cinader Award - Pamela Ohashi" (PDF). Canadian Society for Immunology.
  3. 1 2 3 4 5 6 "Governance - Pamela S. Ohashi, PhD, FRSC". American Association for Cancer Research.
  4. 1 2 "Researcher - Pamela S Ohashi". University Health Network.
  5. ↑ "Faculty - Pamela S Ohashi". Department of Immunology.
  6. ↑ Government of Canada, Industry Canada (2012-11-29). "Canada Research Chairs". www.chairs-chaires.gc.ca. Retrieved 2020-06-11.
  7. ↑ Brunk, Clifford F.; Tsao, Smiley G. S.; Diamond, Catherine H.; Ohashi, Pamela S.; Tsao, Nora N. G.; Pearlman, Ronald E. (1982-09-01). "Reorganization of unique and repetitive sequences during nuclear development in Tetrahymena thermophila". Canadian Journal of Biochemistry. 60 (9): 847–853. doi:10.1139/o82-107. ISSN   0008-4018. PMID   7172094.
  8. ↑ Ohashi, Pamela S.; Mak, Tak W.; Van den Elsen, Peter; Yanagi, Yusuke; Yoshikai, Yasunobu; Calman, Andrew F.; Terhorst, Cox; Stobo, John D.; Weiss, Arthur (August 1985). "Reconstitution of an active surface T3/T-cell antigen receptor by DNA transfer". Nature. 316 (6029): 606–609. Bibcode:1985Natur.316..606O. doi:10.1038/316606a0. ISSN   0028-0836. PMID   4033759. S2CID   4329876.
  9. ↑ Ohashi, Pamela S.; Wallace, Valerie A.; Broughton, Heather; Ohashi, Cara T.; Ferrick, David A.; Jost, Veronica; Mak, Tak W.; Hengartner, Hans; Pircher, Hanspeter (1990). "Specific deletion of the J-Cδ locus in murine α/β T cell clones and studies using transgenic mice". European Journal of Immunology. 20 (3): 517–522. doi:10.1002/eji.1830200309. ISSN   1521-4141. PMID   2318248. S2CID   84784139.
  10. ↑ Ohashi, Pamela S.; Pircher, Hanspeter; Bürki, Kurt; Zinkernagel, Rolf M.; Hengartner, Hans (August 1990). "Distinct sequence of negative or positive selection implied by thymocyte T-cell receptor densities". Nature. 346 (6287): 861–863. Bibcode:1990Natur.346..861O. doi:10.1038/346861a0. ISSN   0028-0836. PMID   1975427. S2CID   4241143.
  11. ↑ Kawai, Kazuhiro; Ohashi, Pamela S. (March 1995). "Immunological function of a defined T-cell population tolerized to low-affinity self antigens". Nature. 374 (6517): 68–69. Bibcode:1995Natur.374...68K. doi:10.1038/374068a0. ISSN   0028-0836. PMID   7870174. S2CID   4325817.
  12. ↑ Ohashi, Pamela S.; Oehen, Stephan; Buerki, Kurt; Pircher, Hanspeter; Ohashi, Cara T.; Odermatt, Bernhard; Malissen, Bernard; Zinkernagel, Rolf M.; Hengartner, Hans (April 1991). "Ablation of "tolerance" and induction of diabetes by virus infection in viral antigen transgenic mice". Cell. 65 (2): 305–317. doi:10.1016/0092-8674(91)90164-T. PMID   1901764. S2CID   8293666.
  13. ↑ Speiser, Daniel E.; Miranda, Renata; Zakarian, Arsen; Bachmann, Martin F.; McKall-Faienza, Kim; Odermatt, Bernhard; Hanahan, Douglas; Zinkernagel, Rolf M.; Ohashi, Pamela S. (1997-08-29). "Self Antigens Expressed by Solid Tumors Do Not Efficiently Stimulate Naive or Activated T Cells: Implications for Immunotherapy". Journal of Experimental Medicine. 186 (5): 645–653. doi:10.1084/jem.186.5.645. ISSN   0022-1007. PMC   2199023 . PMID   9271580.
  14. ↑ Nguyen, Linh T.; Elford, Alisha R.; Murakami, Kiichi; Garza, Kristine M.; Schoenberger, Stephen P.; Odermatt, Bernhard; Speiser, Daniel E.; Ohashi, Pamela S. (2002-02-18). "Tumor Growth Enhances Cross-Presentation Leading to Limited T Cell Activation without Tolerance". Journal of Experimental Medicine. 195 (4): 423–435. doi:10.1084/jem.20010032. ISSN   1540-9538. PMC   2193619 . PMID   11854356.
  15. ↑ Dissanayake, Dilan; Hall, Håkan; Berg-Brown, Nancy; Elford, Alisha R; Hamilton, Sara R; Murakami, Kiichi; Deluca, Leslie Summers; Gommerman, Jennifer L; Ohashi, Pamela S (December 2011). "Nuclear factor-κB1 controls the functional maturation of dendritic cells and prevents the activation of autoreactive T cells". Nature Medicine. 17 (12): 1663–1667. doi:10.1038/nm.2556. ISSN   1078-8956. PMID   22081022. S2CID   1245361.
  16. ↑ Johnson, Dylan J.; Ohashi, Pamela S. (May 2013). "Molecular programming of steady-state dendritic cells: impact on autoimmunity and tumor immune surveillance: Molecular programming of steady-state dendritic cells". Annals of the New York Academy of Sciences. 1284 (1): 46–51. doi:10.1111/nyas.12114. PMID   23651192. S2CID   5095794.
  17. ↑ "Clinical Trial Ohashi". BioCanRx. 2016-10-12. Retrieved 2020-06-11.
  18. ↑ "CCS honours Canada's best cancer researchers - Canadian Cancer Society". www.cancer.ca. Retrieved 2020-06-11.
  19. ↑ "SITC Expands Global Reach, Elects Key Opinion Leaders to the Board - Society for Immunotherapy of Cancer (SITC)". www.sitcancer.org. Retrieved 2020-06-11.
  20. ↑ "Award Winners". Canadian Society for Immunology.
  21. ↑ "Fellows | Page 89 | The Royal Society of Canada". rsc-src.ca. 3 August 2012. Retrieved 2020-06-11.
  22. ↑ "AAI-PharMingen Investigator Award". American Association of Immunology.
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