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. Cleary SJ, Qiu L, Seo Y, Baluk P, Liu D, Serwas NK, Taylor CA, Zhang D, Cyster JG, McDonald DM, Krummel MF, Looney MR. Intravital imaging of pulmonary lymphatics in inflammation and metastatic cancer. J Exp Med. 2025 May 05; 222(5).  View on PubMed
  2. Ray A, Hu KH, Kersten K, Courau T, Kuhn NF, Zaleta-Linares I, Samad B, Combes AJ, Krummel MF. Targeting CD206+ macrophages disrupts the establishment of a key antitumor immune axis. J Exp Med. 2025 Jan 06; 222(1).  View on PubMed
  3. Spottiswoode N, Tsitsiklis A, Chu VT, Phan HV, DeVoe C, Love C, Ghale R, Bloomstein J, Zha BS, Maguire CP, Glascock A, Sarma A, Mourani PM, Kalantar KL, Detweiler A, Neff N, Haller SC, COMET Consortium, DeRisi JL, Erle DJ, Hendrickson CM, Kangelaris KN, Krummel MF, Matthay MA, Woodruff PG, Calfee CS, Langelier CR. Microbial dynamics and pulmonary immune responses in COVID-19 secondary bacterial pneumonia. Nat Commun. 2024 Oct 29; 15(1):9339.  View on PubMed
  4. Cleary SJ, Qiu L, Seo Y, Baluk P, Liu D, Serwas NK, Cyster JG, McDonald DM, Krummel MF, Looney MR. Intravital imaging of pulmonary lymphatics in inflammation and metastatic cancer. bioRxiv. 2024 Sep 17.  View on PubMed
  5. Magnen M, You R, Rao AA, Davis RT, Rodriguez L, Bernard O, Simoneau CR, Hysenaj L, Hu KH, Maishan M, Conrad C, Gbenedio OM, Samad B, Consortium TUC, Love C, Woodruff PG, Erle DJ, Hendrickson CM, Calfee CS, Matthay MA, Roose JP, Sil A, Ott M, Langelier CR, Krummel MF, Looney MR. Immediate myeloid depot for SARS-CoV-2 in the human lung. Sci Adv. 2024 Aug 02; 10(31):eadm8836.  View on PubMed
  6. Kuhn NF, Zaleta-Linares I, Nyberg WA, Eyquem J, Krummel MF. Localized in vivo gene editing of murine cancer-associated fibroblasts. bioRxiv. 2024 Jul 16.  View on PubMed
  7. Neyton LPA, Patel RK, Sarma A, UCSF COMET Consortium, Willmore A, Haller SC, Kangelaris KN, Eckalbar WL, Erle DJ, Krummel MF, Hendrickson CM, Woodruff PG, Langelier CR, Calfee CS, Fragiadakis GK. Distinct pulmonary and systemic effects of dexamethasone in severe COVID-19. Nat Commun. 2024 Jun 28; 15(1):5483.  View on PubMed
  8. Ray A, Hu KH, Kersten K, Courau T, Kuhn NF, Zaleta-Linares I, Samad B, Combes AJ, Krummel MF. Critical role of CD206+ macrophages in promoting a cDC1-NK-CD8 T cell anti-tumor immune axis. bioRxiv. 2024 Jun 17.  View on PubMed
  9. Ray A, Bassette M, Hu KH, Pass LF, Samad B, Combes A, Johri V, Davidson B, Hernandez G, Zaleta-Linares I, Krummel MF. Multimodal identification of rare potent effector CD8 T cells in solid tumors. bioRxiv. 2023 Sep 28.  View on PubMed
  10. 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
  11. Hackney JA, Shivram H, Vander Heiden J, Overall C, Orozco L, Gao X, Kim E, West N, Qamra A, Chang D, Chakrabarti A, Choy DF, Combes AJ, Courau T, Fragiadakis GK, Rao AA, Ray A, Tsui J, Hu K, Kuhn NF, Krummel MF, Erle DJ, Kangelaris K, Sarma A, Lyon Z, Calfee CS, Woodruff PG, Ghale R, Mick E, Byrne A, Zha BS, Langelier C, Hendrickson CM, van der Wijst MGP, Hartoularos GC, Grant T, Bueno R, Lee DS, Greenland JR, Sun Y, Perez R, Ogorodnikov A, Ward A, Ye CJ, UCSF COMET Consortium, Ramalingam T, McBride JM, Cai F, Teterina A, Bao M, Tsai L, Rosas IO, Regev A, Kapadia SB, Bauer RN, Rosenberger CM. A myeloid program associated with COVID-19 severity is decreased by therapeutic blockade of IL-6 signaling. iScience. 2023 Oct 20; 26(10):107813.  View on PubMed
  12. 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
  13. 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
  14. Neyton LPA, Patel RK, Sarma A, UCSF COMET Consortium, Willmore A, Haller SC, Kangelaris KN, Eckalbar WL, Erle DJ, Krummel MF, Hendrickson CM, Woodruff PG, Langelier CR, Calfee CS, Fragiadakis GK. Distinct pulmonary and systemic effects of dexamethasone in severe COVID-19. Res Sq. 2023 Aug 03.  View on PubMed
  15. 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
  16. 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
  17. 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
  18. 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 06 27; 42(6):112582.  View on PubMed
  19. 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
  20. 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

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