Susan Kaech, PhD
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Contact Info
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
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)
Research at a Glance
Yale Co-Authors
Publications Timeline
Curtis Jamison Perry, MD, PhD
Joseph Craft, MD
Katerina Politi, PhD
Robert Homer, MD, PhD
Brinda Emu, MD
Hailong Meng, PhD
Publications
2024
ARID1A suppresses R-loop-mediated STING-type I interferon pathway activation of anti-tumor immunity
Maxwell M, Hom-Tedla M, Yi J, Li S, Rivera S, Yu J, Burns M, McRae H, Stevenson B, Coakley K, Ho J, Gastelum K, Bell J, Jones A, Eskander R, Dykhuizen E, Shadel G, Kaech S, Hargreaves D. ARID1A suppresses R-loop-mediated STING-type I interferon pathway activation of anti-tumor immunity. Cell 2024, 187: 3390-3408.e19. PMID: 38754421, PMCID: PMC11193641, DOI: 10.1016/j.cell.2024.04.025.Peer-Reviewed Original ResearchCitationsAltmetricConceptsImmune checkpoint blockadeAnti-tumor immunityIncreased CD8+ T cell infiltrationCD8+ T cell infiltrationT cell infiltrationType I IFN signalingGene expression signaturesICB treatmentCheckpoint blockadeIndependent of microsatellite instabilityARID1A mutationsCytolytic activityImmune phenotypeMurine modelCell infiltrationARID1A lossClinical trialsMutant cancersARID1AHuman cancersExpression signaturesGene upregulationMicrosatellite instabilityCancerInterferonEGFR-driven lung adenocarcinomas coopt alveolar macrophage metabolism and function to support EGFR signaling and growth.
Kuhlmann-Hogan A, Cordes T, Xu Z, Kuna R, Traina K, Robles-Oteiza C, Ayeni D, Kwong E, Levy S, Globig A, Nobari M, Cheng G, Leibel S, Homer R, Shaw R, Metallo C, Politi K, Kaech S. EGFR-driven lung adenocarcinomas coopt alveolar macrophage metabolism and function to support EGFR signaling and growth. Cancer Discovery 2024, 14: 524-545. PMID: 38241033, DOI: 10.1158/2159-8290.cd-23-0434.Peer-Reviewed Original ResearchCitationsConceptsLung adenocarcinomaGM-CSFEGFR-mutant lung adenocarcinomaGM-CSF secretionProinflammatory immune responseSuppress tumor progressionLocal immunosuppressionStatin therapyTherapeutic combinationsNovel therapiesTumor cellsTumor progressionTumor growthLung adenocarcinoma cellsEGFR phosphorylationImmune responseTransformed epitheliumCancer cellsInflammatory functionsEGFR signalingMacrophage metabolismAlveolar macrophagesIncreased cholesterol synthesisMetabolic supportOncogenic signalingEGFR-Driven Lung Adenocarcinomas Co-opt Alveolar Macrophage Metabolism and Function to Support EGFR Signaling and Growth.
Kuhlmann-Hogan A, Cordes T, Xu Z, Kuna R, Traina K, Robles-Oteíza C, Ayeni D, Kwong E, Levy S, Globig A, Nobari M, Cheng G, Leibel S, Homer R, Shaw R, Metallo C, Politi K, Kaech S. EGFR-Driven Lung Adenocarcinomas Co-opt Alveolar Macrophage Metabolism and Function to Support EGFR Signaling and Growth. Cancer Discovery 2024, of1-of22. PMID: 38270272, DOI: 10.1158/2159-8290.cd-23-0434.Peer-Reviewed Original ResearchCitationsAltmetricConceptsLung adenocarcinomaGM-CSFEGFR-mutant lung adenocarcinomaT cell-based immunotherapyTransformed epitheliumOncogenic signalingGM-CSF secretionProinflammatory immune responseSuppress tumor progressionLocal immunosuppressionStatin therapyTherapeutic combinationsNovel therapiesTumor cellsTumor progressionTumor growthLung cancerLung adenocarcinoma cellsEGFR phosphorylationImmune responseImmunological supportCancer cellsInflammatory functionsAlveolar macrophagesIncreased cholesterol synthesis
2023
Early Chromatin Remodeling Events in Acutely Stimulated CD8+ T Cells
McDonald B, Chick B, Hargreaves D, Kaech S. Early Chromatin Remodeling Events in Acutely Stimulated CD8+ T Cells. The Yale Journal Of Biology And Medicine 2023, 96: 467-473. PMID: 38161581, PMCID: PMC10751865, DOI: 10.59249/axgu7370.Peer-Reviewed Original ResearchAltmetric1014 Adrenergic receptors regulate T cell differentiation in viral infection and cancer
Globig A, Zhao S, Roginsky J, Avina-Ochoa N, Heeg M, Chaudhary O, Hoffmann F, Chen D, O’Connor C, Emu B, Kaech S. 1014 Adrenergic receptors regulate T cell differentiation in viral infection and cancer. 2023, a1122-a1122. DOI: 10.1136/jitc-2023-sitc2023.1014.Peer-Reviewed Original Research
2014
The Transcription Factor FoxO1 Sustains Expression of the Inhibitory Receptor PD-1 and Survival of Antiviral CD8+ T Cells during Chronic Infection
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, 41: 802-814. PMID: 25464856, PMCID: PMC4270830, DOI: 10.1016/j.immuni.2014.10.013.Peer-Reviewed Original ResearchCitationsAltmetricMeSH Keywords and ConceptsMeSH KeywordsAnimalsAntibodies, BlockingAntibodies, MonoclonalCD28 AntigensCD8-Positive T-LymphocytesCell DifferentiationCell Line, TumorChronic DiseaseForkhead Box Protein O1Forkhead Transcription FactorsGranzymesHumansInterferon-gammaJurkat CellsLymphocyte ActivationLymphocytic ChoriomeningitisLymphocytic choriomeningitis virusMiceMice, Inbred C57BLMice, TransgenicProgrammed Cell Death 1 ReceptorProto-Oncogene Proteins c-aktReceptors, Antigen, T-CellSirolimusT-Lymphocytes, CytotoxicTOR Serine-Threonine KinasesConceptsChronic viral infectionsVirus-specific CTLPD-1Viral infectionMurine lymphocytic choriomeningitis virus infectionInhibitory receptor PD-1Lymphocytic choriomeningitis virus infectionCell death protein 1Receptor PD-1Death protein 1MTOR inhibitor rapamycinExhausted CTLsAntiviral CD8Activation of AktInhibitory receptorsTranscription factor FOXO1Chronic infectionT cellsT lymphocytesTherapeutic effectVirus infectionPersistent infectionPositive feedback pathwayInfectionCTLCD4+ T Cell Help Guides Formation of CD103+ Lung-Resident Memory CD8+ T Cells during Influenza Viral Infection
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, 41: 633-645. PMID: 25308332, PMCID: PMC4324721, DOI: 10.1016/j.immuni.2014.09.007.Peer-Reviewed Original ResearchCitationsAltmetricMeSH Keywords and ConceptsConceptsT cellsTRM cellsT-betTissue-resident memory T cellsLung-resident memory CD8T cell-dependent signalsT cell-derived interferonTranscription factor T-betLung Trm cellsMemory T cellsInfluenza viral infectionInfluenza virus infectionT cell helpHeterosubtypic challengeCD103 expressionMemory CD8Respiratory infectionsMucosal sitesCell helpAirway epitheliumVirus infectionViral infectionInfectionLung airwaysImpaired abilityChronic viral infection promotes sustained Th1-derived immunoregulatory IL-10 via BLIMP-1
Parish IA, Marshall HD, Staron MM, Lang PA, Brüstle A, Chen JH, Cui W, Tsui YC, Perry C, Laidlaw BJ, Ohashi PS, Weaver CT, Kaech SM. Chronic viral infection promotes sustained Th1-derived immunoregulatory IL-10 via BLIMP-1. Journal Of Clinical Investigation 2014, 124: 3455-3468. PMID: 25003188, PMCID: PMC4109559, DOI: 10.1172/jci66108.Peer-Reviewed Original ResearchCitationsAltmetricMeSH Keywords and ConceptsMeSH KeywordsAnimalsChronic DiseaseCytokinesInflammation MediatorsInterleukin-10Lymphocytic ChoriomeningitisLymphocytic choriomeningitis virusMAP Kinase Signaling SystemMiceMice, Inbred C57BLMice, KnockoutMice, TransgenicPositive Regulatory Domain I-Binding Factor 1Receptors, Antigen, T-CellTh1 CellsT-Lymphocyte SubsetsTranscription FactorsConceptsChronic viral infectionsIL-10 expressionT cell responsesIL-10 productionIL-10Th1 cellsViral infectionT cellsBlimp-1Viral-specific T cell responsesChronic lymphocytic choriomeningitis virus (LCMV) infectionAntiviral T cell responsesCell responsesImmunosuppressive cytokine IL-10Virus-specific T cellsLymphocytic choriomeningitis virus infectionChronic LCMV infectionImmunoregulatory IL-10Relevant cellular sourceCytokine IL-10Effector T cellsLCMV-infected micePersistent viral infectionT cell compartmentT cell functionImmune-Based Antitumor Effects of BRAF Inhibitors Rely on Signaling by CD40L and IFNγ
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 Research 2014, 74: 3205-3217. PMID: 24736544, PMCID: PMC4063281, DOI: 10.1158/0008-5472.can-13-3461.Peer-Reviewed Original ResearchCitationsAltmetricMeSH Keywords and ConceptsMeSH KeywordsAnimalsAntigen-Presenting CellsAntineoplastic AgentsCD40 LigandCD4-Positive T-LymphocytesDrug Screening Assays, AntitumorIndolesInterferon-gammaMacrophagesMelanoma, ExperimentalMiceMice, TransgenicMutation, MissenseProto-Oncogene Proteins B-rafSignal TransductionSkin NeoplasmsSulfonamidesTumor MicroenvironmentConceptsTumor-infiltrating lymphocytesIFNγ expressionMyeloid cellsImmune stimulatory microenvironmentTh1 effector functionRegulatory T cellsAgonistic CD40 antibodyImmune-related changesTumor-bearing miceSuppress tumor growthIFNγ blockadeImmunologic changesAntitumor immunityAntitumor responseCD40 antibodyTumor regressionT cellsBRAF inhibitorsMurine modelEffector functionsImmunosuppressive featuresAntitumor effectsHost immunityMelanoma growthTumor growthTLR4 Ligands Lipopolysaccharide and Monophosphoryl Lipid A Differentially Regulate Effector and Memory CD8+ T Cell Differentiation
Cui W, Joshi NS, Liu Y, Meng H, Kleinstein SH, Kaech SM. TLR4 Ligands Lipopolysaccharide and Monophosphoryl Lipid A Differentially Regulate Effector and Memory CD8+ T Cell Differentiation. The Journal Of Immunology 2014, 192: 4221-4232. PMID: 24659688, PMCID: PMC4071140, DOI: 10.4049/jimmunol.1302569.Peer-Reviewed Original ResearchCitationsAltmetricMeSH Keywords and ConceptsConceptsT cell differentiationT cellsEffector cellsTLR ligandsToll/IL-1R domain-containing adapterClonal expansionMore memory T cellsMemory T cellsT cell memoryEffector cell expansionTLR4 ligand LPSMonophosphoryl lipid ARole of adjuvantsTLR4 ligand lipopolysaccharideCell differentiationGene expression signaturesMemory CD8LPS-TLR4TLR4 ligandMonophosphoryl lipidLigand LPSLigand lipopolysaccharideAb productionSecondary infectionCell memory
Academic Achievements and Community Involvement
activity Co-PI: Batu Erman at Sabanci University HIV, HCV, WHO
ResearchDetails01/01/2010 - 01/01/2012TurkeyAbstract/SynopsisTranscriptional Control of IL-7 Receptor (IL-7R) in T Cells
honor HHMI Early Career Scientist
UnknownHHMIDetails01/01/2009United Stateshonor Presidential Early Career Award for Scientists and Engineers (PECASE)
UnknownDetails01/01/2007United Stateshonor American Asthma Foundation Investigator Award
UnknownDetails01/01/2007United Stateshonor Cancer Research Institute Investigator Award
UnknownCRIDetails01/01/2005United States
Links & Media
Media
Formation of memory T cells following infection.
Upon infection, naïve T cells become activated and proliferate and differentiate into a heterogeneous population of effector T cells. Most of the effector T cells terminally differentiate into effector T cells (blue cells) that protect against the current infection, but lose potential to develop into memory T cells. A smaller subset of effector T cells persist to develop into different types of memory T cells such as effector memory T (TEM) cells (red), central memory T (TCM) cells (yellow) and resident memory T (TRM) cells (green). These different populations of memory T cells form a tiered defense system. Figure modified from: Cui W and Kaech SM. Transcriptional Regulation of Effector and Memory CD8 T cell fates. Nat Rev Immunol 12:749-61 (2012).
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Locations
Kaech Lab
Lab
The Anlyan Center
300 Cedar Street, Ste S640
New Haven, CT 06519
Appointments
203.785.7661