Research Summary

Important discoveries come from fundamental research and 'How does this work' questions. For the past 15 years, I have studied mechanisms that regulate T cell responses and therefore regulate immune function, using cutting-edge real-time imaging methods to ask these kinds of questions. As a graduate student, I developed expertise in the generation and use of monoclonal antibodies targeted to costimulatory and inhibitory molecules on T cells. One of these projects developed antibodies to CTLA-4, which not only identified an inhibitory pathway of T cell regulation but also could be used to trigger or block that pathway. I subsequently applied these antibodies toward upregulating T cell responses to antigens in vivo and then toward augmenting immune responses to tumors. That approach led to the development of human antibodies of the same type, a therapy now named ipilimumab, and progressing toward FDA approval for treatment of melanoma and other cancers. I am firmly convinced that there is considerably more to be done with respect to modulating signaling in tumor microenvironments.

My lab now focuses on figuring out how immune systems--collections of cells in complex tissues--work. Our work capitalizes on using fluorescent proteins to track information processing by the immune system using imaging and/or flow cytometry. This has frequently taken the form of tagging and modulating components of the T cell receptor complex to understand the dynamics of signaling, as well as tagging and modulating motor proteins and other cytoskeletal proteins to study how these dynamics are controlled. These approaches have profited from considerable investments in developing novel imaging approaches. In addition, my lab emphasizes the use of fluorescent imaging approaches to understand how information is exchanged in the dense cellular milieu of organs.

We have developed imaging approaches to allow us to track T lymphocytes in lymph nodes, pancreas, lungs, and tumors. These are revealing unexpected dynamics of the assembly of complexes of lymphocytes and are paving the way to the types of studies defined herein--where key lymphocytes and stromal components begin again to be targeted with antibodies to disrupt interactions that likely control the local response. One exceptionally useful approach that we've developed is the generation of spontaneous models of breast cancer in which the stromal cells that interact with tumors become fluorescent by virtue of the uptake of very stable fluorescent protein variants. This enables us to focus on specific phagocytes in the tumor microenvironments and begin to characterize them as primary players in transmitting signals to lymphocytes and regulating disease outcome.

We continue to seek ways to understand basic biology and then facile means to translate that understanding into mechanisms for improving selectivity in the immune response.

Research Funding

  • April 1, 2008 - March 31, 2023 - Understanding Asthma Endotypes , Co-Investigator . Sponsor: NIH, Sponsor Award ID: U19AI077439
  • June 15, 2015 - May 31, 2020 - Manipulating collectivity and Niches for Developing CD8 Immunity , Principal Investigator . Sponsor: NIH, Sponsor Award ID: R01AI114787
  • September 1, 2015 - August 31, 2018 - Living Tumor Biopsies to Interrogate Immune Function and Response to Therapy , Principal Investigator . Sponsor: NIH, Sponsor Award ID: R21CA196468
  • September 15, 2002 - December 31, 2017 - Cytoskeletal Regulation of T cell Motility and Synaptic Signaling , Principal Investigator . Sponsor: NIH, Sponsor Award ID: R01AI052116
  • September 23, 2011 - July 31, 2017 - Leukocyte Biomarkers for Predicting Human Breast Cancer Outcomes , Principal Investigator . Sponsor: NIH, Sponsor Award ID: U54CA163123
  • January 1, 2015 - December 31, 2016 - CUTTING EDGE LINEAGE TRACKING OF TUMOR-EDUCATED IMMUNE CELLS , Principal Investigator . Sponsor: NIH, Sponsor Award ID: R21CA191428
  • January 1, 2012 - December 31, 2016 - Epithelial Progenitor Cells in Lung Repair and Regeneration , Principal Investigator . Sponsor: NIH, Sponsor Award ID: U01HL111054
  • July 1, 1979 - March 31, 2016 - Evolving Microenvironments in Airway Inflammation , Co-Investigator . Sponsor: NIH, Sponsor Award ID: P01HL024136
  • September 1, 2009 - August 31, 2014 - Collaborative Innate-Adaptive Immune Regulation of Tumor Progression , Principal Investigator . Sponsor: NIH, Sponsor Award ID: U01CA141451
  • May 1, 2012 - April 30, 2014 - Defining the First Hours of Lung metastasis using Intravital Live-Imaging , Principal Investigator . Sponsor: NIH, Sponsor Award ID: R21CA167601
  • June 5, 2011 - June 4, 2013 - Multiphoton Instrumentation for Translational Assays from Human Tissue Biopsies , Principal Investigator . Sponsor: NIH, Sponsor Award ID: S10RR029266
  • July 17, 2009 - June 30, 2011 - Regulation of T cell Functions by the Breast Cancer Microenvironment , Principal Investigator . Sponsor: NIH, Sponsor Award ID: R01CA134622
  • April 1, 2008 - March 31, 2010 - New Models for Molecular-Level Imaging of Cell Signaling in vivo. , Principal Investigator . Sponsor: NIH, Sponsor Award ID: R21RR024895
  • March 1, 2005 - February 28, 2008 - Imaging-Based Analysis of Tolerance-Induction Mechanisms , Principal Investigator . Sponsor: NIH, Sponsor Award ID: R21AI062899
  • March 21, 1998 - October 14, 2000 - GENES ASSOCIATED WITH POSTTHYMIC T CELL DIFFERENTIATION , Principal Investigator . Sponsor: NIH, Sponsor Award ID: F32AI010120

Education

University of Illinois at Champaign-Urbana, B.S.+B.S., 1985-1989, Biology and Chemistry
University of California at Berkeley, Ph.D., 1989-1995, Immunology
Walter and Eliza Hall Institute, Melbourne Aus., 1996-1997, Immunology
Stanford University, 1997-2001, Immunology

Honors & Awards

  • 1986
    University of Illinois: James Scholar
  • 1996-1997
    Postdoctoral Fellowship, Juvenile Diabetes Foundation International
  • 1997-2000
    NRSA Postdoctoral Fellowship, National Institutes of Health
  • 2004-2007
    Investigator Award, Cancer Research Institute

Selected Publications

  1. Patel RK, Jaszczak RG, Im K, Carey ND, Courau T, Bunis DG, Samad B, Avanesyan L, Chew NW, Stenske S, Jespersen JM, Publicover J, Edwards AW, Naser M, Rao AA, Lupin-Jimenez L, Krummel MF, Cooper S, Baron JL, Combes AJ, Fragiadakis GK. Cyclone: an accessible pipeline to analyze, evaluate, and optimize multiparametric cytometry data. Front Immunol. 2023; 14:1167241.  View on PubMed
  2. Reina-Campos M, Heeg M, Kennewick K, Mathews IT, Galletti G, Luna V, Nguyen Q, Huang H, Milner JJ, Hu KH, Vichaidit A, Santillano N, Boland BS, Chang JT, Jain M, Sharma S, Krummel MF, Chi H, Bensinger SJ, Goldrath AW. Metabolic programs of T cell tissue residency empower tumour immunity. Nature. 2023 Sep; 621(7977):179-187.  View on PubMed
  3. Juric V, Mayes E, Binnewies M, Lee T, Canaday P, Pollack JL, Rudolph J, Du X, Liu VM, Dash S, Palmer R, Jahchan NS, Ramoth ÅJ, Lacayo S, Mankikar S, Norng M, Brassell C, Pal A, Chan C, Lu E, Sriram V, Streuli M, Krummel MF, Baker KP, Liang L. TREM1 activation of myeloid cells promotes antitumor immunity. Sci Transl Med. 2023 08 30; 15(711):eadd9990.  View on PubMed
  4. Fragiadakis G, Neyton L, Patel R, Sarma A, Consortium UC, Willmore A, Haller SC, Kangelaris K, Eckalbar W, Erle D, Krummel M, Hendrickson C, Woodruff P, Langelier C, Calfee C. Distinct pulmonary and systemic effects of dexamethasone in severe COVID-19. Res Sq. 2023 Aug 03.  View on PubMed
  5. Tanaka M, Lum L, Hu K, Ledezma-Soto C, Samad B, Superville D, Ng K, Adams Z, Kersten K, Fong L, Combes AJ, Krummel M, Reeves M. Tumor cell heterogeneity drives spatial organization of the intratumoral immune response in squamous cell skin carcinoma. bioRxiv. 2023 Jun 21.  View on PubMed
  6. Combes AJ, Samad B, Krummel MF. Defining and using immune archetypes to classify and treat cancer. Nat Rev Cancer. 2023 07; 23(7):491-505.  View on PubMed
  7. Hu KH, Kuhn NF, Courau T, Tsui J, Samad B, Ha P, Kratz JR, Combes AJ, Krummel MF. Transcriptional space-time mapping identifies concerted immune and stromal cell patterns and gene programs in wound healing and cancer. Cell Stem Cell. 2023 06 01; 30(6):885-903.e10.  View on PubMed
  8. Kersten K, You R, Liang S, Tharp KM, Pollack J, Weaver VM, Krummel MF, Headley MB. Uptake of tumor-derived microparticles induces metabolic reprogramming of macrophages in the early metastatic lung. Cell Rep. 2023 May 30; 42(6):112582.  View on PubMed
  9. Munson PV, Adamik J, Hartmann FJ, Favaro PMB, Ho D, Bendall SC, Combes AJ, Krummel MF, Zhang K, Kelley RK, Butterfield LH. Polyunsaturated Fatty Acid-Bound α-Fetoprotein Promotes Immune Suppression by Altering Human Dendritic Cell Metabolism. Cancer Res. 2023 05 02; 83(9):1543-1557.  View on PubMed
  10. Im KW, Huppert LA, Malevanchik L, Rugo HS, Combes AJ, Campbell MJ, Krummel MF, Melisko ME. High-dimensional immune cell profiling of cerebrospinal fluid from patients with metastatic breast cancer and leptomeningeal disease. NPJ Breast Cancer. 2023 Apr 07; 9(1):22.  View on PubMed
  11. Rahim MK, Okholm TLH, Jones KB, McCarthy EE, Liu CC, Yee JL, Tamaki SJ, Marquez DM, Tenvooren I, Wai K, Cheung A, Davidson BR, Johri V, Samad B, O'Gorman WE, Krummel MF, van Zante A, Combes AJ, Angelo M, Fong L, Algazi AP, Ha P, Spitzer MH. Dynamic CD8+ T cell responses to cancer immunotherapy in human regional lymph nodes are disrupted in metastatic lymph nodes. Cell. 2023 03 16; 186(6):1127-1143.e18.  View on PubMed
  12. Marsan E, Velmeshev D, Ramsey A, Patel RK, Zhang J, Koontz M, Andrews MG, de Majo M, Mora C, Blumenfeld J, Li AN, Spina S, Grinberg LT, Seeley WW, Miller BL, Ullian EM, Krummel MF, Kriegstein AR, Huang EJ. Astroglial toxicity promotes synaptic degeneration in the thalamocortical circuit in frontotemporal dementia with GRN mutations. J Clin Invest. 2023 03 15; 133(6).  View on PubMed
  13. Patel RK, Jaszczak RG, Kwok I, Carey ND, Courau T, Bunis D, Samad B, Avanesyan L, Chew NW, Stenske S, Jespersen JM, Publicover J, Edwards A, Naser M, Rao AA, Lupin-Jimenez L, Krummel MF, Cooper S, Baron J, Combes AJ, Fragiadakis GK. Cyclone: an accessible pipeline to analyze, evaluate and optimize multiparametric cytometry data. bioRxiv. 2023 Mar 11.  View on PubMed
  14. Hysenaj L, Little S, Kulhanek K, Magnen M, Bahl K, Gbenedio OM, Prinz M, Rodriguez L, Andersen C, Rao AA, Shen A, Lone JC, Lupin-Jimenez LC, Bonser LR, Serwas NK, Mick E, Khalid MM, Taha TY, Kumar R, Li JZ, Ding VW, Matsumoto S, Maishan M, Sreekumar B, Simoneau C, Nazarenko I, Tomlinson MG, Khan K, von Gottberg A, Sigal A, Looney MR, Fragiadakis GK, Jablons DM, Langelier CR, Matthay M, Krummel M, Erle DJ, Combes AJ, Sil A, Ott M, Kratz JR, Roose JP. SARS-CoV-2 infection of airway organoids reveals conserved use of Tetraspanin-8 by Ancestral, Delta, and Omicron variants. Stem Cell Reports. 2023 03 14; 18(3):636-653.  View on PubMed
  15. Beppler C, Eichorst J, Marchuk K, Cai E, Castellanos CA, Sriram V, Roybal KT, Krummel MF. Hyperstabilization of T cell microvilli contacts by chimeric antigen receptors. J Cell Biol. 2023 03 06; 222(3).  View on PubMed
  16. Joffre J, Rodriguez L, Matthay ZA, Lloyd E, Fields AT, Bainton RJ, Kurien P, Sil A, Calfee CS, Woodruff PG, Erle DJ, Hendrickson C, Krummel MF, Langelier CR, Matthay MA, Kornblith LZ, Hellman J, COVID-19 Multi-Phenotyping for Effective Therapies (COMET) Consortium, COVID-19 Associated Coagulopathy, Inflammation, and Thrombosis (Co-ACIT) Study Group. COVID-19-associated Lung Microvascular Endotheliopathy: A "From the Bench" Perspective. Am J Respir Crit Care Med. 2022 10 15; 206(8):961-972.  View on PubMed
  17. Adamik J, Munson PV, Hartmann FJ, Combes AJ, Pierre P, Krummel MF, Bendall SC, Argüello RJ, Butterfield LH. Distinct metabolic states guide maturation of inflammatory and tolerogenic dendritic cells. Nat Commun. 2022 09 02; 13(1):5184.  View on PubMed
  18. Yi R, Chen E, Roberts EW, Krummel MF, Serwas NK. Impact of protein identity on tumor-associated antigen uptake into infiltrating immune cells: A comparison of different fluorescent proteins as model antigens. PLoS One. 2022; 17(8):e0272857.  View on PubMed
  19. Cai E, Beppler C, Eichorst J, Marchuk K, Eastman SW, Krummel MF. T cells use distinct topographical and membrane receptor scanning strategies that individually coalesce during receptor recognition. Proc Natl Acad Sci U S A. 2022 08 09; 119(32):e2203247119.  View on PubMed
  20. Burnett CE, Okholm TLH, Tenvooren I, Marquez DM, Tamaki S, Munoz Sandoval P, Willmore A, UCSF COMET Consortium, Hendrickson CM, Kangelaris KN, Langelier CR, Krummel MF, Woodruff PG, Calfee CS, Erle DJ, Ansel KM, Spitzer MH. Mass cytometry reveals a conserved immune trajectory of recovery in hospitalized COVID-19 patients. Immunity. 2022 07 12; 55(7):1284-1298.e3.  View on PubMed

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