University of California San Francisco
Helen Diller Family Comprehensive Cancer Center
Matthew F. Krummel, PhD

Matthew F. Krummel, PhD

Associate Professor, Department of Pathology, UCSF
Robert E. Smith Endowed Chair in Experimental Pathology, UCSF

Cancer Center Program Memberships

Cancer Immunology

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.

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


Professional Experience

  • Summer 1987
    Summer Undergraduate Research Fellow. University of Texas Health Science Center at Dallas
  • Summer 1988
    Stagiare (Technician) Institut Pasteur, Paris, Unite de Genie Micro-Biologique
  • Aug 1989-May 1995
    Graduate Student, University of California at Berkeley, Department of Molecular and Cell Biology
  • June 1995-May 1996
    Postdoctoral Fellow, University of California at Berkeley
  • Aug 1996-Sept 1997
    Postdoctoral Fellow, Walter and Eliza Hall Institute of Medical Research, Melbourne Australia
  • Nov 1997-August 2001
    Postdoctoral Fellow, Beckman Institute, Stanford University, Stanford, CA
  • August 2001-2006
    Assistant Professor, Department of Pathology, University of California at San Francisco
  • July 2006-present
    Associate Professor, Department of Pathology, University of California at San Francisco

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. Krummel MF, Mahale JN, Uhl LFK, Hardison EA, Mujal AM, Mazet JM, Weber RJ, Gartner ZJ, Gérard A. Paracrine costimulation of IFN-? signaling by integrins modulates CD8 T cell differentiation. Proc Natl Acad Sci U S A. 2018 Oct 22.
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  2. Barry KC, Hsu J, Broz ML, Cueto FJ, Binnewies M, Combes AJ, Nelson AE, Loo K, Kumar R, Rosenblum MD, Alvarado MD, Wolf DM, Bogunovic D, Bhardwaj N, Daud AI, Ha PK, Ryan WR, Pollack JL, Samad B, Asthana S, Chan V, Krummel MF. A natural killer-dendritic cell axis defines checkpoint therapy-responsive tumor microenvironments. Nat Med. 2018 Jun 25.
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  3. Binnewies M, Roberts EW, Kersten K, Chan V, Fearon DF, Merad M, Coussens LM, Gabrilovich DI, Ostrand-Rosenberg S, Hedrick CC, Vonderheide RH, Pittet MJ, Jain RK, Zou W, Howcroft TK, Woodhouse EC, Weinberg RA, Krummel MF. Understanding the tumor immune microenvironment (TIME) for effective therapy. Nat Med. 2018 May; 24(5):541-550.
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  4. Loo K, Tsai KK, Mahuron K, Liu J, Pauli ML, Sandoval PM, Nosrati A, Lee J, Chen L, Hwang J, Levine LS, Krummel MF, Algazi AP, Pampaloni M, Alvarado MD, Rosenblum MD, Daud AI. Partially exhausted tumor-infiltrating lymphocytes predict response to combination immunotherapy. JCI Insight. 2017 07 20; 2(14).
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  5. Cai E, Marchuk K, Beemiller P, Beppler C, Rubashkin MG, Weaver VM, Gérard A, Liu TL, Chen BC, Betzig E, Bartumeus F, Krummel MF. Visualizing dynamic microvillar search and stabilization during ligand detection by T cells. Science. 2017 05 12; 356(6338).
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  6. Tumeh PC, Hellmann MD, Hamid O, Tsai KK, Loo KL, Gubens MA, Rosenblum M, Harview CL, Taube JM, Handley N, Khurana N, Nosrati A, Krummel MF, Tucker A, Sosa EV, Sanchez PJ, Banayan N, Osorio JC, Nguyen-Kim DL, Chang J, Shintaku IP, Boasberg PD, Taylor EJ, Munster PN, Algazi AP, Chmielowski B, Dummer R, Grogan TR, Elashoff D, Hwang J, Goldinger SM, Garon EB, Pierce RH, Daud A. Liver Metastasis and Treatment Outcome with Anti-PD-1 Monoclonal Antibody in Patients with Melanoma and NSCLC. Cancer Immunol Res. 2017 05; 5(5):417-424.
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  7. Lefrançais E, Ortiz-Muñoz G, Caudrillier A, Mallavia B, Liu F, Sayah DM, Thornton EE, Headley MB, David T, Coughlin SR, Krummel MF, Leavitt AD, Passegué E, Looney MR. The lung is a site of platelet biogenesis and a reservoir for haematopoietic progenitors. Nature. 2017 04 06; 544(7648):105-109.
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  8. Boldajipour B, Nelson A, Krummel MF. Tumor-infiltrating lymphocytes are dynamically desensitized to antigen but are maintained by homeostatic cytokine. JCI Insight. 2016 12 08; 1(20):e89289.
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  9. Roberts EW, Broz ML, Binnewies M, Headley MB, Nelson AE, Wolf DM, Kaisho T, Bogunovic D, Bhardwaj N, Krummel MF. Critical Role for CD103(+)/CD141(+) Dendritic Cells Bearing CCR7 for Tumor Antigen Trafficking and Priming of T Cell Immunity in Melanoma. Cancer Cell. 2016 08 08; 30(2):324-336.
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  10. Headley MB, Bins A, Nip A, Roberts EW, Looney MR, Gerard A, Krummel MF. Visualization of immediate immune responses to pioneer metastatic cells in the lung. Nature. 2016 Mar 24; 531(7595):513-7.
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  11. Krummel MF, Bartumeus F, Gérard A. T cell migration, search strategies and mechanisms. Nat Rev Immunol. 2016 03; 16(3):193-201.
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  12. Plaks V, Boldajipour B, Linnemann JR, Nguyen NH, Kersten K, Wolf Y, Casbon AJ, Kong N, van den Bijgaart RJ, Sheppard D, Melton AC, Krummel MF, Werb Z. Adaptive Immune Regulation of Mammary Postnatal Organogenesis. Dev Cell. 2015 Sep 14; 34(5):493-504.
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  13. Hashimoto M, Yanagisawa H, Minagawa S, Sen D, Ma R, Murray LA, Tsui P, Lou J, Marks JD, Baron JL, Krummel MF, Nishimura SL. TGF-ß-Dependent Dendritic Cell Chemokinesis in Murine Models of Airway Disease. J Immunol. 2015 Aug 01; 195(3):1182-90.
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  14. Broz ML, Krummel MF. The emerging understanding of myeloid cells as partners and targets in tumor rejection. Cancer Immunol Res. 2015 Apr; 3(4):313-9.
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  15. Hashimoto M, Yanagisawa H, Minagawa S, Sen D, Goodsell A, Ma R, Moermans C, McKnelly KJ, Baron JL, Krummel MF, Nishimura SL. A critical role for dendritic cells in the evolution of IL-1ß-mediated murine airway disease. J Immunol. 2015 Apr 15; 194(8):3962-9.
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  16. Broz ML, Binnewies M, Boldajipour B, Nelson AE, Pollack JL, Erle DJ, Barczak A, Rosenblum MD, Daud A, Barber DL, Amigorena S, Van't Veer LJ, Sperling AI, Wolf DM, Krummel MF. Dissecting the tumor myeloid compartment reveals rare activating antigen-presenting cells critical for T cell immunity. Cancer Cell. 2014 Nov 10; 26(5):638-52.
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  17. Gérard A, Patino-Lopez G, Beemiller P, Nambiar R, Ben-Aissa K, Liu Y, Totah FJ, Tyska MJ, Shaw S, Krummel MF. Detection of rare antigen-presenting cells through T cell-intrinsic meandering motility, mediated by Myo1g. Cell. 2014 Jul 31; 158(3):492-505.
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  18. Lelkes E, Headley MB, Thornton EE, Looney MR, Krummel MF. The spatiotemporal cellular dynamics of lung immunity. Trends Immunol. 2014 Aug; 35(8):379-86.
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  19. Krummel MF, Friedman RS, Jacobelli J. Modes and mechanisms of T cell motility: roles for confinement and Myosin-IIA. Curr Opin Cell Biol. 2014 Oct; 30:9-16.
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  20. Patnode ML, Bando JK, Krummel MF, Locksley RM, Rosen SD. Leukotriene B4 amplifies eosinophil accumulation in response to nematodes. J Exp Med. 2014 Jun 30; 211(7):1281-8.
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