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Susan Kaech, PhD

Professor Adjunct-Immunobiology
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About

Titles

Professor Adjunct-Immunobiology

Biography

Education

Stanford University Ph.D., Developmental Biology 1993-1998
University of Washington, Seattle, WA B.S., Cellular and Molecular Biology 1989-1993

Professional Experience

1990-1991 Undergraduate Researcher, Div. of Basic Sciences, Fred Hutchinson Cancer Research Center
1991-1993 Undergraduate Researcher, Dept. of Zoology, University of Washington, Seattle
1993-1998 Graduate Student, Dept. of Developmental Biology, Stanford University

1999-2004 Postdoctoral Fellow, Dept. of Microbiology and Immunology and Emory Vaccine Center, Emory University
2004-2009 Assistant Professor, Department of Immunobiology, Yale University

2009-2015 Associate Professor, Department of Immunobiology, Yale University

2015-present Professor, Department of Immunobiology, Yale University

2009-2015 HHMI Early Career Scientist



Honors and Awards

National Science Foundation Predoctoral Fellowship 1993-1996

Damon Runyon-Walter Winchell Cancer Research Fellowship 1999-2002

Burroughs-Wellcome Foundation Award in Biomedical Sciences 2003-2008

Edward Mallinckrodt Jr. Foundation Award 2005-2008

Cancer Research Institute Investigator Award 2005-2009

American Asthma Foundation Investigator 2007-2010

Presidential Early Career Award for Scientists and Engineers (PECASE) 2007

Howard Hughes Early Career Scientist 2009-2015




Appointments

Education & Training

PhD
Stanford University (1998)
BS
University of Washington, Cellular and Molecular Biology (1993)

Research

Overview

What are the decisive factors that determine which effector cells survive to become long-lived memory cells and which cells die during the contraction phase? We have characterized the transcriptome of effector and memory T cells and identified genetic pathways and several transcription factors that regulate this life or death decision in activated T cells. Our work has helped to outline a model of effector T cell differentiation wherein a small subset of T cells develop into memory precursor cells that are more fit to persist following the first infection than the majority of effector cells. These memory precursor cells develop into long-lived memory T cells that protect against re-infection. Several types of memory T cells, which differ by their phenotypes, functions and anatomical locations, are produced to create a sophisticated, multi-layered defense system. Conceptually, the memory T cells are divided into three subsets: (1) Tissue resident memory T (TRM) cells, which locally reside in mucosal tissues to provide the front line of defense against pathogens that breach our barriers; (2) Effector memory T (TEM) cells, which circulate through the blood and tissues and are rapidly recruited to the sites of inflammation upon reinfection; and (3) central memory T (TCM) cells, which circulate through the blood and lymphoid organs to produce a second wave of effector T cells upon reinfection. TCM cell populations also contain multipotent “memory stem cells" that self-renew to sustain the memory T cell population over time.

Despite this general knowledge, we lack a deep understanding of how different types of memory T cells are generated during an immune response and persist thereafter to provide protective immunity upon reinfection. Such knowledge will have a significant impact on the development of vaccines and immunotherapies to fight infectious disease, cancer, and autoimmunity. My lab has spent the last decade elucidating regulatory pathways that control whether an effector T cell lives and adopts memory cell fates or terminally differentiates into shorter-lived effector cells and dies. These discoveries have shown that memory T cell fate determination is influenced by environmental cues and a balance of inflammatory and anti-inflammatory cytokines. Currently, my lab is trying to understand how signals in the tissue microenvironment and nutrient availability governs changes in gene expression, epigenetic remodeling and memory T cell metabolism that regulate the types of memory T cells that form and their homeostasis following infection (Figure 1). Work in this area will not only reveal basic principles in the generation and maintenance of memory T cells, but will also enhance our understanding of broad biological principles in tissue and tissue stem cell homeostasis, tumor microenvironments, and control of cellular metabolism by environmental conditions. Currently, we are focusing on several fundamental questions surrounding the development of protective memory T cells to fight infectious disease and cancer.

First, little is known about how tissues specify memory T cell properties and regulate their long-term survival and homeostasis. To develop a multilayered defense system, TCM, TEM and TRM cells must distribute themselves broadly and adopt tissue-specific properties dictated by their environments. We do not understand even basic aspects of how this occurs: for example, what are the relevant tissue-trophic factors and cell types that govern this? We are trying to elucidate the key components of the tissue microenvironment that direct transcriptional and epigenetic changes in memory T cells as they undergo environmental adaptation to different tissues and inflammatory conditions. This work is paramount to developing vaccines with tissue-targeting precision that protect against different routes of pathogen entry (e.g., airways, skin, genitals, and blood).

A second major gap exists in our understanding of the metabolic determinants of memory T cell longevity and self-renewal. We know very little about the metabolic and nutrient-utilization pathways that regulate survival and self-renewal of the different memory T cell subsets in various tissues. One recent breakthrough is our discovery that triglyceride storage is essential for the longevity and self-renewal of memory T cells. We are studying how lipid synthesis and storage are regulated in memory T cells by T cell growth factors and tissue environments. In addition to the relevance to T cell biology, this work will likely reveal conserved paradigms for metabolic control of stem cell longevity and self-renewal in general.

Third, our understanding of the functional and metabolic connections between T cells and tumors is in its infancy. Central goals of our work are to understand how T cells are regulated by the tumor microenvironment and determine if the metabolic rate of the tumor itself modulates that of the infiltrating T cells. We are also addressing the novel concept that nutrient competition between the T cells and tumor cells is a key component of immunosuppression in the tumor microenvironment. We will also examine an unexplored process of tumor “metabolic editing”, to determine if T cell immunosurveillance actually selects for cancer cells with higher metabolic rates and intensifies nutrient competition, paradoxically promoting tumor progression.

Memory CD8 T cell differentiation

Memory CD4 T cell differentiation

Chronic viral infection

Tumor Immunology and Immunotherapy

Medical Subject Headings (MeSH)

Developmental Biology; Global Health; Infectious Disease Medicine; T-Lymphocytes; Vaccines

Research at a Glance

Yale Co-Authors

Frequent collaborators of Susan Kaech's published research.

Publications

2024

2023

2014

Academic Achievements & Community Involvement

  • activity

    Co-PI: Batu Erman at Sabanci University HIV, HCV, WHO

  • honor

    HHMI Early Career Scientist

  • honor

    Presidential Early Career Award for Scientists and Engineers (PECASE)

  • honor

    American Asthma Foundation Investigator Award

  • honor

    Cancer Research Institute Investigator Award

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