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

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. 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
  2. You R, Artichoker J, Ray A, Gonzalez Velozo H, Rock DA, Conner KP, Krummel MF. Visualizing Spatial and Stoichiometric Barriers to Bispecific T-Cell Engager Efficacy. Cancer Immunol Res. 2022 Jun 03; 10(6):698-712.  View on PubMed
  3. 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, COMET consortium and the Co-ACIT Study Group
    . COVID-19-Associated Lung Microvascular Endotheliopathy: A "From the Bench" Perspective. Am J Respir Crit Care Med. 2022 Jun 01.  View on PubMed
  4. Kersten K, Hu KH, Combes AJ, Samad B, Harwin T, Ray A, Rao AA, Cai E, Marchuk K, Artichoker J, Courau T, Shi Q, Belk J, Satpathy AT, Krummel MF. Spatiotemporal co-dependency between macrophages and exhausted CD8+ T cells in cancer. Cancer Cell. 2022 06 13; 40(6):624-638.e9.  View on PubMed
  5. Laviron M, Petit M, Weber-Delacroix E, Combes AJ, Arkal AR, Barthélémy S, Courau T, Hume DA, Combadière C, Krummel MF, Boissonnas A. Tumor-associated macrophage heterogeneity is driven by tissue territories in breast cancer. Cell Rep. 2022 May 24; 39(8):110865.  View on PubMed
  6. Looney M, Magnen M, You R, Rao A, Davis R, Rodriguez L, Simoneau C, Hysenaj L, Hu K, Love C, Woodruff P, Erle D, Hendrickson C, Calfee C, Matthay M, Roose J, Sil A, Ott M, Langelier C, Krummel M. Immediate myeloid depot for SARS-CoV-2 in the human lung. Res Sq. 2022 May 17.  View on PubMed
  7. Magnen M, You R, Rao AA, Davis RT, Rodriguez L, Simoneau CR, Hysenaj L, Hu KH, UCSF COMET Consortium, 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. bioRxiv. 2022 May 11.  View on PubMed
  8. Mujal AM, Combes AJ, Rao AA, Binnewies M, Samad B, Tsui J, Boissonnas A, Pollack JL, Argüello RJ, Meng MV, Porten SP, Ruhland MK, Barry KC, Chan V, Krummel MF. Holistic Characterization of Tumor Monocyte-to-Macrophage Differentiation Integrates Distinct Immune Phenotypes in Kidney Cancer. Cancer Immunol Res. 2022 04 01; 10(4):403-419.  View on PubMed
  9. Burnett CE, Okholm TLH, Tenvooren I, Marquez DM, Tamaki S, Sandoval PM, UCSF COMET Consortium, Calfee CS, Hendrickson CM, Kangelaris KN, Langelier CR, Krummel MF, Woodruff PG, Erle DJ, Ansel KM, Spitzer MH. A conserved immune trajectory of recovery in hospitalized COVID-19 patients. bioRxiv. 2022 Mar 16.  View on PubMed
  10. Combes AJ, Samad B, Tsui J, Chew NW, Yan P, Reeder GC, Kushnoor D, Shen A, Davidson B, Barczak AJ, Adkisson M, Edwards A, Naser M, Barry KC, Courau T, Hammoudi T, Argüello RJ, Rao AA, Olshen AB, Immunoprofiler Consortium, Cai C, Zhan J, Davis KC, Kelley RK, Chapman JS, Atreya CE, Patel A, Daud AI, Ha P, Diaz AA, Kratz JR, Collisson EA, Fragiadakis GK, Erle DJ, Boissonnas A, Asthana S, Chan V, Krummel MF. Discovering dominant tumor immune archetypes in a pan-cancer census. Cell. 2022 01 06; 185(1):184-203.e19.  View on PubMed
  11. Kratz JR, Li JZ, Tsui J, Lee JC, Ding VW, Rao AA, Mann MJ, Chan V, Combes AJ, Krummel MF, Jablons DM. Genetic and immunologic features of recurrent stage I lung adenocarcinoma. Sci Rep. 2021 12 08; 11(1):23690.  View on PubMed
  12. Tsitsiklis A, Zha BS, Byrne A, DeVoe C, Rackaityte E, Levan S, Sunshine S, Mick E, Ghale R, Love C, Tarashansky AJ, Pisco A, Albright J, Jauregui A, Sarma A, Neff N, Serpa PH, Deiss TJ, Kistler A, Carrillo S, Ansel KM, Leligdowicz A, Christenson S, Detweiler A, Jones NG, Wu B, Darmanis S, Lynch SV, DeRisi JL, COMET Consortium, Matthay MA, Hendrickson CM, Kangelaris KN, Krummel MF, Woodruff PG, Erle DJ, Rosenberg O, Calfee CS, Langelier CR. Impaired immune signaling and changes in the lung microbiome precede secondary bacterial pneumonia in COVID-19. medRxiv. 2021 Nov 30.  View on PubMed
  13. Binnewies M, Pollack JL, Rudolph J, Dash S, Abushawish M, Lee T, Jahchan NS, Canaday P, Lu E, Norng M, Mankikar S, Liu VM, Du X, Chen A, Mehta R, Palmer R, Juric V, Liang L, Baker KP, Reyno L, Krummel MF, Streuli M, Sriram V. Targeting TREM2 on tumor-associated macrophages enhances immunotherapy. Cell Rep. 2021 10 19; 37(3):109844.  View on PubMed
  14. Im K, Combes AJ, Spitzer MH, Satpathy AT, Krummel MF. Archetypes of checkpoint-responsive immunity. Trends Immunol. 2021 11; 42(11):960-974.  View on PubMed
  15. Jiang H, Courau T, Borison J, Ritchie AJ, Mayer AT, Krummel MF, Collisson EA. Activating Immune Recognition in Pancreatic Ductal Adenocarcinoma via Autophagy Inhibition, MEK Blockade, and CD40 Agonism. Gastroenterology. 2022 02; 162(2):590-603.e14.  View on PubMed
  16. You R, Artichoker J, Fries A, Edwards AW, Combes AJ, Reeder GC, Samad B, Krummel MF. Active surveillance characterizes human intratumoral T cell exhaustion. J Clin Invest. 2021 09 15; 131(18).  View on PubMed
  17. Weiner J, Suwalski P, Holtgrewe M, Rakitko A, Thibeault C, Müller M, Patriki D, Quedenau C, Krüger U, Ilinsky V, Popov I, Balnis J, Jaitovich A, Helbig ET, Lippert LJ, Stubbemann P, Real LM, Macías J, Pineda JA, Fernandez-Fuertes M, Wang X, Karadeniz Z, Saccomanno J, Doehn JM, Hübner RH, Hinzmann B, Salvo M, Blueher A, Siemann S, Jurisic S, Beer JH, Rutishauser J, Wiggli B, Schmid H, Danninger K, Binder R, Corman VM, Mühlemann B, Arjun Arkal R, Fragiadakis GK, Mick E, Comet C, Calfee CS, Erle DJ, Hendrickson CM, Kangelaris KN, Krummel MF, Woodruff PG, Langelier CR, Venkataramani U, García F, Zyla J, Drosten C, Alice B, Jones TC, Suttorp N, Witzenrath M, Hippenstiel S, Zemojtel T, Skurk C, Poller W, Borodina T, Pa-Covid SG, Ripke S, Sander LE, Beule D, Landmesser U, Guettouche T, Kurth F, Heidecker B. Increased risk of severe clinical course of COVID-19 in carriers of HLA-C*04:01. EClinicalMedicine. 2021 Oct; 40:101099.  View on PubMed
  18. Mehta P, Gouirand V, Boda DP, Zhang J, Gearty SV, Zirak B, Lowe MM, Clancy S, Boothby I, Mahuron KM, Fries A, Krummel MF, Mankoo P, Chang HW, Liu J, Moreau JM, Scharschmidt TC, Daud A, Kim E, Neuhaus IM, Harris HW, Liao W, Rosenblum MD. Layilin Anchors Regulatory T Cells in Skin. J Immunol. 2021 10 01; 207(7):1763-1775.  View on PubMed
  19. Sarma A, Christenson SA, Byrne A, Mick E, Pisco AO, DeVoe C, Deiss T, Ghale R, Zha BS, Tsitsiklis A, Jauregui A, Moazed F, Detweiler AM, Spottiswoode N, Sinha P, Neff N, Tan M, Serpa PH, Willmore A, Ansel KM, Wilson JG, Leligdowicz A, Siegel ER, Sirota M, DeRisi JL, Matthay MA, COMET Consortium, Hendrickson CM, Kangelaris KN, Krummel MF, Woodruff PG, Erle DJ, Calfee CS, Langelier CR. Tracheal aspirate RNA sequencing identifies distinct immunological features of COVID-19 ARDS. Nat Commun. 2021 08 26; 12(1):5152.  View on PubMed
  20. van der Wijst MGP, Vazquez SE, Hartoularos GC, Bastard P, Grant T, Bueno R, Lee DS, Greenland JR, Sun Y, Perez R, Ogorodnikov A, Ward A, Mann SA, Lynch KL, Yun C, Havlir DV, Chamie G, Marquez C, Greenhouse B, Lionakis MS, Norris PJ, Dumont LJ, Kelly K, Zhang P, Zhang Q, Gervais A, Le Voyer T, Whatley A, Si Y, Byrne A, Combes AJ, Rao AA, Song YS, Fragiadakis GK, Kangelaris K, Calfee CS, Erle DJ, Hendrickson C, Krummel MF, Woodruff PG, Langelier CR, Casanova JL, Derisi JL, Anderson MS, Ye CJ, UCSF COMET consortium. Type I interferon autoantibodies are associated with systemic immune alterations in patients with COVID-19. Sci Transl Med. 2021 Sep 22; 13(612):eabh2624.  View on PubMed

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