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OMB No. 0925-0001/0002 (Rev. 08/12 Approved Through 8/31/2015)
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NAME: Kaech, Susan
eRA COMMONS USER NAME (agency login):
POSITION TITLE: Professor of Immunobiology
EDUCATION/TRAINING (Begin with baccalaureate or other initial professional education, such as nursing,
include postdoctoral training and residency training if applicable.)
INSTITUTION AND LOCATION
DEGREE
(if applicable)
Completion
MM/YYYY
University of Washington, Seattle, WA
Stanford University, Stanford, CA
BS
PHD
05/1993
05/1998
Date FIELD OF STUDY
Cellular and Molecular Biology
Developmental Biology
A. Personal Statement
Immunological memory is one of the cardinal hallmarks of our immune system and Dr. Kaech is a leading
authority in the area of effector and memory T cell development during viral and bacterial infections. Her lab
elucidates basic principals underlying the development of long-lived memory T cells following infection, and
has been a major leader in identifying the genetic pathways that regulate the formation of virus-specific effector
and memory T cells during acute and chronic viral infection. Her labs work has provided considerable
mechanistic insight into the process of generating long-lived memory T cells during infection. Dr. Kaech has
extensive experience studying T cell responses to acute and chronic lymphocytic choriomeningitis virus
(LCMV), Listeria and more recently influenza infection. Through this work, her lab has made several seminal
discoveries on the regulation of CD8 and CD4 memory T cell differentiation. In particular, her work has
distinguished cellular precursors of long-lived memory CD8 T cells and has begun to elucidate the
transcriptional networks that control their differentiation. This has led to the identification of important regulators
such as T-bet, Blimp-1, Zeb2, Bcl-6, FoxO1, and STAT3 in this process. Her lab has also identified key
cytokines (such as IL-12, IL-10 and IL-21) that regulate effector and memory cell fate decisions. Using gene
expression profiling, her lab has built gene signature databases that serve as a rich resource for the field to
identify candidate signals and genetic pathways that promote the development of memory T cells and their
precursors. Dr. Kaech has provided insight into the types of CD4 T cells that form during viral infection and has
begun to delineate signals that regulate TH1 and TFH cell differentiation during viral infection. More recently,
her lab has made a new inroads into understanding how particular types of memory T cells that reside in
mucosal tissues, referred to as resident memory T cells (TRM cells), form in the lung following influenza
infection. Additionally, Dr. Kaech is pioneering new work in understanding the metabolic regulation of T cells
and how their differentiation and functional states are altered by nutrient availability during infection and in
tumors.
1.
Ho P-C, Binhuniak JD, Macintyre AN, Staron MM, Liu X, Amezquita R, Tsui Y-C, Micevic G, Perales
JC, Klenstein SH, Abel ED, Insogna KL, Feske S, Locasale JW, Bosenberg MW, Rathmell JC, Kaech SM.
Phosphoenolpyruvate is a metabolic checkpoint controlling Ca2+-NFAT signaling and anti-tumor T cell
responses. In press, Cell (2015).
2.
Cui G, Staron MM, Gray SM, Ho PC, Amezquita RA, Wu J, Kaech SM. IL-7-Induced Glycerol Transport
and TAG Synthesis Promotes Memory CD8(+) T Cell Longevity. Cell. 2015 May 7;161(4):750-61. PubMed
PMID: 25957683. PubMed Central PMCID: in progress.
3.
Chen JH, Perry CJ, Tsui YC, Staron MM, Parish IA, Dominguez CX, Rosenberg DW, Kaech SM.
Prostaglandin E2 and programmed cell death 1 signaling coordinately impair CTL function and survival during
chronic viral infection. Nat Med. 2015 Apr;21(4):327-34. PubMed PMID: 25799228. PubMed Central PMCID: in
progress.
4.
Staron MM, Gray SM, Marshall HD, Parish IA, Chen JH, Perry CJ, Cui G, Li MO, Kaech SM. The
transcription factor FoxO1 sustains expression of the inhibitory receptor PD-1 and survival of antiviral CD8(+) T
cells during chronic infection. Immunity. 2014 Nov 20;41(5):802-14. PubMed PMID: 25464856; PubMed
Central PMCID: PMC4270830.
B. Positions and Honors
Positions and Employment
1993 - 1998
1999 - 2004
2004 - 2009
2009 - 2015
2009 - 2015
2015 -
Graduate Student, Dept. of Developmental Biology, Stanford University
Postdoctoral Fellow, Dept. of Microbiology and Immunology & Emory Vaccine Center, Emory
University
Assistant Professor, Department of Immunobiology, Yale University
Howard Hughes Medical Institute Early Career Scientist, Yale University
Associate Professor (with Tenure 2011), Dept. of Immunobiology, Yale University
Professor of Immunobiology, Yale University, New Haven, CT
Other Experience and Professional Memberships
2006 2007 - 2009
2009 2010 - 2010
2011 2012 2013 -
Editorial Board Member, Journal of Immunology and Cell Biology
Associate Editor, Journal of Immunology
Member, American Association for the Advancement of Science
BSC ad hoc Reviewer, NIA, Laboratory of Immunology
Regular Member, American Assoc. of Immunologists (AAI)
Permanent Member, CMI-B study section
Section Editor, Journal of Immunology
Honors
1999
2003
2005
2005
2007
2007
2009
Damon Runyon-Walter Winchell Cancer Research Fellowship, Damon Runyon-Walter Winchell
Cancer Research Foundation
Burroughs-Wellcome Foundation Award in Biomedical Science, Burroughs-Wellcome
Foundation
Edward Mallinckrodt Jr. Foundation Award , Edward Mallinckrodt Jr. Foundation
Investigator Award , Cancer Research Institute (CRI)
American Asthma Foundation Early Investigator
Presidential Early Career Award for Scientists & Engineers (PECASE), NIH
HHMI Early Career Scientist, Howard Hughes Medical Institute @Yale University
C. Contribution to Science
1. Identification of IL-7R+ memory CD8 T cell precursors and the core transcriptional machinery that
controls effector and memory T cell differentiation and metabolism. My lab has been a leader in
elucidating the signaling and transcriptional pathways that govern memory T cell differentiation and
specification over the past decade. I helped discover the cellular progenitors of long-lived memory CD8 T
cells (i.e., memory precursor (MP) cells) that form following viral infection in mice based on increased
expression of the IL-7 receptor alpha (IL-7Rα), which is functionally required for their development into
mature memory CD8 T cells. My lab has profiled the transcriptional changes that occur as naïve CD8 T
cells differentiate into effector cells and then into memory cells, and have identified numerous TFs that
control effector and memory cell fate decisions, including T-bet, Blimp-1, Bcl-6, STAT3 and Zeb2. We
developed a model that several TFs operate in a graded manner to control TE vs MP fates, which provides
a mechanism for how heterogeneous effector CD8 T cell pools arise during immune responses. Likewise,
we found that graded expression of T-bet controlled CD4 the balance between T helper 1 (TH1) and T
follicular helper (TFH) cell specification. These findings provided a paradigm for the generation of effector
and memory T cells, akin to a rheostat, in which their differentiation is influenced by graded amounts of
inflammation and expression of TFs. Collectively, this work has lead to a premiere understanding of the
transcriptional circuitry that underlies generation of effector and memory cell fates. We are currently
investigating how epigenetic changes control the changes in gene expression associated with memory cell
longevity and plasticity, and how this integrates with cellular metabolism. More recently, we have identified
an essential role for IL-7 signaling in maintaining triacylglyceride (TAG) homeostasis in memory CD8 T
cells to promote their long-term survival via a glycerol transporter Aquaporin-9 (Aqp9).
a. Joshi NS, Cui W, Chandele A, Lee HK, Urso DR, Hagman J, Gapin L, Kaech SM. Inflammation directs
memory precursor and short-lived effector CD8(+) T cell fates via the graded expression of T-bet
transcription factor. Immunity. 2007 Aug;27(2):281-95. PubMed PMID: 17723218; PubMed Central
PMCID: PMC2034442.
b. Rutishauser RL, Martins GA, Kalachikov S, Chandele A, Parish IA, Meffre E, Jacob J, Calame K,
Kaech SM. Transcriptional repressor Blimp-1 promotes CD8(+) T cell terminal differentiation and
represses the acquisition of central memory T cell properties. Immunity. 2009 Aug 21;31(2):296-308.
PubMed PMID: 19664941; PubMed Central PMCID: PMC2783637.
c. Marshall HD, Chandele A, Jung YW, Meng H, Poholek AC, Parish IA, Rutishauser R, Cui W, Kleinstein
SH, Craft J, Kaech SM. Differential expression of Ly6C and T-bet distinguish effector and memory Th1
CD4(+) cell properties during viral infection. Immunity. 2011 Oct 28;35(4):633-46. PubMed PMID:
22018471; PubMed Central PMCID: PMC3444169.
d. Cui G, Staron MM, Gray SM, Ho PC, Amezquita RA, Wu J, Kaech SM. IL-7-Induced Glycerol
Transport and TAG Synthesis Promotes Memory CD8(+) T Cell Longevity. Cell. 2015 May
7;161(4):750-61. PubMed PMID: 25957683. PubMed Central PMCID: in progress.
2. Elucidating how pro-inflammatory and anti-inflammatory cytokines regulate CD8 and CD4 effector
and memory T cell fates. An important question is how particular T cell fates are specified during the
course of infection in which the cells are exposed to numerous types of signals that can influence T cell
differentiation and function. Which signals are key determinants to generating different types of effector
and memory CD8 T cells is a central question in the field of T cell biology and immunological memory. It is
well known that several pro-inflammatory cytokines, such as IL-12, IL-2 and type I IFNs enhance CTL
differentiation, but our lab and others have shown that these cytokines can also influence whether effector
CD8 T cells develop into memory precursor cells or terminal effector cells depending on the intensity or
duration of cytokine signaling. In CD4 T cells we have identified how the such signals promote the
development of TH1 cells over TFH cells. Greater exposure to such signals enhances the expression or
activity of transcription factors that instruct terminal differentiation of CTLs or TH1 cells, thereby
suppressing the formation of memory cells and their progenitors or TFH cells. In contrast, anti-inflammatory
cytokines such as IL-10 and TGFβ enhance memory CD8 T cell development in circulation and the
mucosa, respectively. We have also found that TGFβ counterbalances IL-2 signaling to promote the
differentiation of T follicular helper (TFH) CD4+ T cells in the lung mucosa. Together, these findings help
frame a paradigm that the balance between pro-inflammatory and anti-inflammatory signals is critical to
memory CD8 T cell development. More recently we have identified that IL-10 production by Tregs is critical
for generating protective circulating memory T cells, thus identifying a new role for Tregs in host defense.
a. Cui W, Liu Y, Weinstein JS, Craft J, Kaech SM. An interleukin-21-interleukin-10-STAT3 pathway is
critical for functional maturation of memory CD8+ T cells. Immunity. 2011 Nov 23;35(5):792-805.
PubMed PMID: 22118527; PubMed Central PMCID: PMC3431922.
b. Ray JP, Marshall HD, Laidlaw BJ, Staron MM, Kaech SM, Craft J. Transcription factor STAT3 and type
I interferons are corepressive insulators for differentiation of follicular helper and T helper 1 cells.
Immunity. 2014 Mar 20;40(3):367-77. PubMed PMID: 24631156; PubMed Central PMCID:
PMC3992517.
c. Laidlaw BJ, Zhang N, Marshall HD, Staron MM, Guan T, Hu Y, Cauley LS, Craft J, Kaech SM. CD4+ T
cell help guides formation of CD103+ lung-resident memory CD8+ T cells during influenza viral
infection. Immunity. 2014 Oct 16;41(4):633-45. PubMed PMID: 25308332; PubMed Central PMCID:
PMC4324721.
d. Marshall HD, Ray JP, Laidlaw BJ, Zhang N, Gawande D, Staron MM, Craft J, Kaech SM. The
transforming growth factor beta signaling pathway is critical for the formation of CD4 T follicular helper
cells and isotype-switched antibody responses in the lung mucosa. Elife. 2015 Jan 8;4:e04851.
PubMed PMID: 25569154; PubMed Central PMCID: PMC4337607.
3. Discovering factors that control CD8 T cell exhaustion. Viruses that cause chronic infection have
evolved strategies to evade immune responses and the persistence of antigen can lead to alterations in
CD8 T cell proliferation, survival, effector functions and gene expression that lead to the differentiation of
dysfunctional or ‘exhausted’ CD8 T cells. My lab has also made new inroads into pathways that control
CTL exhaustion and PD-1 expression during chronic viral infection. We have discovered a new pathway
involving PGE2 signaling that suppresses CTLs during chronic infection in concert with PD-1. Blockade of
PGE2 and PD-1 signaling simultaneously augments T cell function more than either treatment alone. This
may be a new combination treatment to consider for rejuvenating T cell function in chronic infection or
cancer. Our lab has also shed a new perspective on T cell exhaustion by finding that decreased PI3K, AKT
and mTOR activity enhances activity of the transcription factor FoxO1 and promotes T cell exhaustion.
Increased FoxO1 activity serves two vital purposes in the activated CD8 T cells: one, to sustain expression
of Bcl-2 and to keep the activated T cells alive, and two, to sustain PD-1 expression and limit TCR
signaling and immunopathology. Thus, maintenance of a FoxO1hi PD-1hi state is a necessary adaptation
that sustains CTL responses during chronic infection and prevents “holes” in the T cell repertoire from
forming. In this manner, FoxO1 regulates T cell stress resistance by helping them cope with alterations in
their external stimuli. Collectively, these findings are of fundamental importance to our understanding T cell
dysfunction during chronic diseases such as HIV and cancer, and serve as a foundation for the
development of novel therapeutics.
a. Wherry EJ, Ha SJ, Kaech SM, Haining WN, Sarkar S, Kalia V, Subramaniam S, Blattman JN, Barber
DL, Ahmed R. Molecular signature of CD8+ T cell exhaustion during chronic viral infection. Immunity.
2007 Oct;27(4):670-84. PubMed PMID: 17950003.
b. Hand TW, Cui W, Jung YW, Sefik E, Joshi NS, Chandele A, Liu Y, Kaech SM. Differential effects of
STAT5 and PI3K/AKT signaling on effector and memory CD8 T-cell survival. Proc Natl Acad Sci U S A.
2010 Sep 21;107(38):16601-6. PubMed PMID: 20823247; PubMed Central PMCID: PMC2944719.
c. Staron MM, Gray SM, Marshall HD, Parish IA, Chen JH, Perry CJ, Cui G, Li MO, Kaech SM. The
transcription factor FoxO1 sustains expression of the inhibitory receptor PD-1 and survival of antiviral
CD8(+) T cells during chronic infection. Immunity. 2014 Nov 20;41(5):802-14. PubMed PMID:
25464856; PubMed Central PMCID: PMC4270830.
d. Chen JH, Perry CJ, Tsui YC, Staron MM, Parish IA, Dominguez CX, Rosenberg DW, Kaech SM.
Prostaglandin E2 and programmed cell death 1 signaling coordinately impair CTL function and survival
during chronic viral infection. Nat Med. 2015 Apr;21(4):327-34. PubMed PMID: 25799228.
4. Elucidating mechanisms of T cell regulation in cancer. The tumor microenvironment is notoriously
immunosuppressive and the holy grail of tumor immunology is to devise methods to restimulate the
immune cells to reject tumor cells and halt tumor progression and death. Through the study of genetically
engineered models of melanoma and lung cancer in mice, we are characterizing the changes that occur in
the immune cells, particularly the tumor associated macrophages (TAMs) and T cells, during chemo- and
immuno-therapies. This work is necessary to understand the action of anti-cancer drugs and identify
targeted therapies that work best in conjunction with immunotherapies, such as PD-1 or CTLA-4 blockade.
We have found that vemurafenib, a targeted inhibitor of the BRafV600E oncogene commonly used to treat
B-RafV600E-mutated melanomas, had robust immunostimulatory properties, specifically on the immune
cells localized in the tumors. We also found that stimulating CD40 alone, using anti-CD40 agonist mAbs,
sufficiently suppressed tumor growth and this occurs in a T cell independent manner by modulating TAMs.
Other new work from the lab is investigating the metabolic control of T cells in the tumor microenvironment
and how this may be an underlying feature of T cell exhaustion in tumors. Together, my lab is making
insight into how the immune microenvironment is regulating tumor growth and contributes to efficacy of
new therapies.
a. Ho P-C, Binhuniak JD, Macintyre AN, Staron MM, Liu X, Amezquita R, Tsui Y-C, Micevic G, Perales
JC, Klenstein SH, Abel ED, Insogna KL, Feske S, Locasale JW, Bosenberg MW, Rathmell JC, Kaech
SM. Phosphoenolpyruvate is a metabolic checkpoint controlling Ca2+-NFAT signaling and anti-tumor T
cell responses. In press, Cell (2015).
b. Ho PC, Meeth KM, Tsui YC, Srivastava B, Bosenberg MW, Kaech SM. Immune-based antitumor
effects of BRAF inhibitors rely on signaling by CD40L and IFNγ. Cancer Res. 2014 Jun 15;74(12):320517. PubMed PMID: 24736544; PubMed Central PMCID: PMC4063281.
D. Research Support
Ongoing Research Support
2015/04/01-2018/03/31
1R01CA195720-01, NIH/NCI
Politi, Katerina and Kaech, Susan (Co-PI)
Targeting the Immune System in Mouse Models of Lung Adenocarcinoma
The goal of this work is to gain a comprehensive understanding of the immune microenvioronment in
genetically engineered mouse modes of mutant EGFR lung adenocarcinoma.
Role: CPI
2013/02/01-2018/01/31
R37 AI066232-11, National Institute of Allergy and Infectious Diseases (NIAID)
Kaech, Susan M (PI)
Regulation of memory CD8 T cell development
Role: PI
2014/07/01-2016/06/30
Clinical Laboratory Integration Program , Cancer Research Institute
Kaech, Susan (PI)
Enhancing immunotherapy-based cancer treatments through CD40-dependent immunomodulation of the
tumor microenvironment.
The goal of this work is to determine how agonistic anti-CD40 mAb treatment promotes anti-tumor immune
responses through modulation of T cells and macrophages in tumors.
Role: PI
2015/04/01-2016/03/31
Co-Pilot Project, Yale Cancer Center
Kathryn Miller-Jensen and Susan Kaech (Co-PI)
Single-cell analysis of tumor-associated macrophage function during melanoma Progression
The goal of this work is to characterize the phenotypic and functional affects on tumor associated
macrophages as melanomas progress and during treatments with agonistic CD40 mAb or CSF1R inhibitors.
Role: CPI