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 M. Nobel notes value of basic research for new drugs. Nature. 2018 11; 563(7730):184.
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  2. 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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  3. Hung LY, Sen D, Oniskey TK, Katzen J, Cohen NA, Vaughan AE, Nieves W, Urisman A, Beers MF, Krummel MF, Herbert DR. Macrophages promote epithelial proliferation following infectious and non-infectious lung injury through a Trefoil factor 2-dependent mechanism. Mucosal Immunol. 2018 Oct 18.
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  4. 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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  5. Babala N, Bovens A, de Vries E, Iglesias-Guimarais V, Ahrends T, Krummel MF, Borst J, Bins AD. Subcellular Localization of Antigen in Keratinocytes Dictates Delivery of CD4+ T-cell Help for the CTL Response upon Therapeutic DNA Vaccination into the Skin. Cancer Immunol Res. 2018 Jul; 6(7):835-847.
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  6. 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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  7. Hung LY, Oniskey TK, Sen D, Krummel MF, Vaughan AE, Cohen NA, Herbert DR. Trefoil Factor 2 Promotes Type 2 Immunity and Lung Repair through Intrinsic Roles in Hematopoietic and Nonhematopoietic Cells. Am J Pathol. 2018 May; 188(5):1161-1170.
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  8. de Mingo Pulido Á, Gardner A, Hiebler S, Soliman H, Rugo HS, Krummel MF, Coussens LM, Ruffell B. TIM-3 Regulates CD103+ Dendritic Cell Function and Response to Chemotherapy in Breast Cancer. Cancer Cell. 2018 Jan 08; 33(1):60-74.e6.
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  9. 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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  10. 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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  11. Yipp BG, Kim JH, Lima R, Zbytnuik LD, Petri B, Swanlund N, Ho M, Szeto VG, Tak T, Koenderman L, Pickkers P, Tool ATJ, Kuijpers TW, van den Berg TK, Looney MR, Krummel MF, Kubes P. The Lung is a Host Defense Niche for Immediate Neutrophil-Mediated Vascular Protection. Sci Immunol. 2017 Apr 28; 2(10).
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  12. 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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  13. 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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  14. Wong PT, Roberts EW, Tang S, Mukherjee J, Cannon J, Nip AJ, Corbin K, Krummel MF, Choi SK. Control of an Unusual Photo-Claisen Rearrangement in Coumarin Caged Tamoxifen through an Extended Spacer. ACS Chem Biol. 2017 04 21; 12(4):1001-1010.
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  15. 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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  16. Starobinets H, Ye J, Broz M, Barry K, Goldsmith J, Marsh T, Rostker F, Krummel M, Debnath J. Antitumor adaptive immunity remains intact following inhibition of autophagy and antimalarial treatment. J Clin Invest. 2016 Dec 01; 126(12):4417-4429.
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  17. Sen D, Jones SM, Oswald EM, Pinkard H, Corbin K, Krummel MF. Tracking the Spatial and Functional Gradient of Monocyte-To-Macrophage Differentiation in Inflamed Lung. PLoS One. 2016; 11(10):e0165064.
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  18. Chong SZ, Evrard M, Devi S, Chen J, Lim JY, See P, Zhang Y, Adrover JM, Lee B, Tan L, Li JL, Liong KH, Phua C, Balachander A, Boey A, Liebl D, Tan SM, Chan JK, Balabanian K, Harris JE, Bianchini M, Weber C, Duchene J, Lum J, Poidinger M, Chen Q, Rénia L, Wang CI, Larbi A, Randolph GJ, Weninger W, Looney MR, Krummel MF, Biswas SK, Ginhoux F, Hidalgo A, Bachelerie F, Ng LG. CXCR4 identifies transitional bone marrow premonocytes that replenish the mature monocyte pool for peripheral responses. J Exp Med. 2016 Oct 17; 213(11):2293-2314.
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  19. Pinkard H, Stuurman N, Corbin K, Vale R, Krummel MF. Micro-Magellan: open-source, sample-adaptive, acquisition software for optical microscopy. Nat Methods. 2016 09 29; 13(10):807-809.
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  20. Loyher PL, Rochefort J, Baudesson de Chanville C, Hamon P, Lescaille G, Bertolus C, Guillot-Delost M, Krummel MF, Lemoine FM, Combadière C, Boissonnas A. CCR2 Influences T Regulatory Cell Migration to Tumors and Serves as a Biomarker of Cyclophosphamide Sensitivity. Cancer Res. 2016 11 15; 76(22):6483-6494.
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