David H Raulet

University of California, Berkeley, Berkeley, California, United States

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Publications (218)2760.15 Total impact

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    ABSTRACT: Increasing evidence supports a role for innate immune effector cells in tumor surveillance. Natural killer (NK) cells and myeloid cells represent the two main subsets of innate immune cells possessing efficient but quite different tumor suppressive abilities. Here, we describe the germline-encoded NK cell receptors that play a role in suppressing tumor development and describe briefly the cellular pathways leading to the upregulation of their ligands in tumor cells. We also describe mechanisms underlying the elimination of tumor cells by macrophages and a recently characterized mechanism dedicated to sensing cytosolic DNA that is implicated in antitumor immune responses.
    No preview · Article · Feb 2016 · Current opinion in immunology
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    ABSTRACT: Recognition and elimination of tumor cells by the immune system is crucial for limiting tumor growth. Natural killer (NK) cells become activated when the receptor NKG2D is engaged by ligands that are frequently upregulated in primary tumors and on cancer cell lines. However, the molecular mechanisms driving NKG2D ligand expression on tumor cells are not well defined. Using a forward genetic screen in a tumor-derived human cell line, we identified several novel factors supporting expression of the NKG2D ligand ULBP1. Our results show stepwise contributions of independent pathways working at multiple stages of ULBP1 biogenesis. Deeper investigation of selected hits from the screen showed that the transcription factor ATF4 drives ULBP1 gene expression in cancer cell lines, while the RNA-binding protein RBM4 supports ULBP1 expression by suppressing a novel alternatively spliced isoform of ULBP1 mRNA. These findings offer insight into the stress pathways that alert the immune system to danger.
    Full-text · Article · Nov 2015 · eLife Sciences
  • David H Raulet

    No preview · Article · Sep 2015 · The Journal of Immunology
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    Michele Ardolino · Joy Hsu · David H Raulet

    Preview · Article · Aug 2015 · Oncotarget
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    Dataset: IMG 1772

    Full-text · Dataset · Jun 2015
  • Michele Ardolino · David H. Raulet
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    ABSTRACT: Recent extraordinary advances in cancer immunotherapy rely primarily on marshaling T cell responses. Here we discuss how NK cell responses can be amplified. We find that MHC I-deficient tumors induce anergy of NK cells but that cytokine therapy restores NK cell activity and increases the survival of mice bearing MHC I-deficient tumors.
    No preview · Article · Jun 2015 · OncoImmunology
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    ABSTRACT: In allogeneic hematopoietic stem cell transplantation (HSCT), controlling graft-versus-host disease (GVHD) while maintaining graft-versus-tumor (GVT) responses is of critical importance. Using a mouse model of allogeneic HSCT, we hereby demonstrate that NKG2D expression by CD8(+) T-cells plays a major role in mediating GVHD and GVT effects by promoting the survival and cytotoxic function of CD8(+) T-cells. The expression of NKG2D ligands was not induced persistently on normal tissues of allogeneic HSCT recipient mice treated with anti-NKG2D antibody, suggesting that transient NKG2D blockade might be sufficient to attenuate GVHD and allow CD8(+) T-cells to regain their GVT function. Indeed, short-term treatment with anti-NKG2D antibody restored GVT effects while maintaining an attenuated GVHD state. NKG2D expression was also detected on CD8(+) T-cells from allogeneic HSCT patients and trended to be higher in those with active GVHD. Together, these data support a novel role for NKG2D expression by CD8(+) T-cells during allogeneic HSCT, which could be potentially therapeutically exploited to separate GVHD from GVT effects. Copyright © 2015 American Society of Hematology.
    Full-text · Article · Apr 2015 · Blood
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    Full-text · Dataset · Mar 2015
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    Full-text · Dataset · Mar 2015
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    ABSTRACT: Immune cells, including natural killer (NK) cells, recognize transformed cells and eliminate them in a process termed immunosurveillance. It is thought that tumor cells evade immunosurveillance by shedding membrane ligands that bind to the NKG2D activating receptor on NK cells and/or T cells, and desensitize these cells. In contrast, we show that in mice, shedding of MULT1, a high affinity NKG2D ligand, causes NK cell activation and tumor rejection. Recombinant soluble MULT1 stimulated tumor rejection in mice. Soluble MULT1 functions, at least in part, by competitively reversing a global desensitization of NK cells imposed by engagement of membrane NKG2D ligands on tumor-associated cells, such as myeloid cells. The results overturn conventional wisdom that soluble ligands are inhibitory, and suggest a new approach for cancer immunotherapy. Copyright © 2015, American Association for the Advancement of Science.
    No preview · Article · Mar 2015 · Science
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    ABSTRACT: Various cytokines have been evaluated as potential anticancer drugs; however, most cytokine trials have shown relatively low efficacy. Here, we found that treatments with IL-12 and IL-18 or with a mutant form of IL-2 (the "superkine" called H9) provided substantial therapeutic benefit for mice specifically bearing MHC class I-deficient tumors, but these treatments were ineffective for mice with matched MHC class I+ tumors. Cytokine efficacy was linked to the reversal of the anergic state of NK cells that specifically occurred in MHC class I-deficient tumors, but not MHC class I+ tumors. NK cell anergy was accompanied by impaired early signal transduction and was locally imparted by the presence of MHC class I-deficient tumor cells, even when such cells were a minor population in a tumor mixture. These results demonstrate that MHC class I-deficient tumor cells can escape from the immune response by functionally inactivating NK cells, and suggest cytokine-based immunotherapy as a potential strategy for MHC class I-deficient tumors. These results suggest that such cytokine therapies would be optimized by stratification of patients. Moreover, our results suggest that such treatments may be highly beneficial in the context of therapies to enhance NK cell functions in cancer patients.
    Preview · Article · Oct 2014 · Journal of Clinical Investigation

  • No preview · Article · Oct 2014 · Cancer Research
  • Nataliya Shifrin · David H. Raulet · Michele Ardolino
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    ABSTRACT: Natural killer (NK) cells represent a first line of defense against pathogens and tumor cells. The activation of NK cells is regulated by the integration of signals deriving from activating and inhibitory receptors expressed on their surface. However, different NK cells respond differently to the same stimulus, be it target cells or agents that crosslink activating receptors. The processes that determine the level of NK cell responsiveness have been referred to collectively as NK cell education. NK cell education plays an important role in steady state conditions, where potentially auto-reactive NK cells are rendered tolerant to the surrounding environment. According to the “tuning” concept, the responsiveness of each NK cell is quantitatively adjusted to ensure self tolerance while at the same time ensuring useful reactivity against potential threats. MHC-specific inhibitory receptors displayed by NK cells play a major role in tuning NK cell responsiveness, but recent studies indicate that signaling from activating receptors is also important, suggesting that the critical determinant is an integrated signal from both types of receptors. An important and still unresolved question is whether NK cell education involves interactions with a specific cell population in the environment. Whether hematopoietic and/or non-hematopoietic cells play a role is still under debate. Recent results demonstrated that NK cell tuning exhibits plasticity in steady state conditions, meaning that it can be re-set if the MHC environment changes. Other evidence suggests, however, that inflammatory conditions accompanying infections may favor high responsiveness, indicating that inflammatory agents can over-ride the natural tendency of NK cells to adjust to the steady state environment. These findings raise many questions such as whether viruses and tumor cells manipulate NK cell responsiveness to evade immune-recognition. As knowledge of the underlying processes grows, the possibility of modulating NK cell responsiveness for therapeutic purposes is becoming increasingly attractive, and is now under serious investigation in clinical studies.
    No preview · Article · Apr 2014 · Seminars in Immunology
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    ABSTRACT: The immunoreceptor NKG2D originally identified in natural killer cells recognizes ligands that are upregulated on tumor cells. Expression of NKG2D ligands (NKG2DLs) is activated by the DNA damage response (DDR) which is often activated constitutively in cancer cells, revealing them to natural killer cells as a mechanism of immunosurveillance. Here we report that the induction of retinoic acid early transcript 1 (RAE1) ligands for NKG2D by the DDR relies on a STING-dependent DNA sensor pathway involving the effector molecules TBK1 and IRF3. Cytosolic DNA was detected in lymphoma cell lines which express RAE1 and its occurrence required activation of the DDR. Transfection of DNA into ligand-negative cells was sufficient to induce RAE1 expression. Irf3+/-;Eμ-Myc mice expressed lower levels of RAE1 on tumor cells and showed a reduced survival rate compared to Irf3+/+;Eμ-Myc mice. Taken together, our results suggest that genomic damage in tumor cells leads to activation of STING-dependent DNA sensor pathways, thereby activating RAE1 and enabling tumor immunosurveillance.
    Full-text · Article · Mar 2014 · Cancer Research
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    ABSTRACT: In recent years, roles of the immune system in immune surveillance of cancer have been explored using a variety of approaches. The roles of the adaptive immune system have been a major emphasis, but increasing evidence supports a role for innate immune effector cells such as natural killer (NK) cells in tumor surveillance. Here, we discuss some of the evidence for roles in tumor surveillance of innate immune cells. In particular, we focus on NK cells and other immune cells that express germline-encoded receptors, often labeled NK receptors. The impact of these receptors and the cells that express them on tumor suppression is summarized. We discuss in detail some of the pathways and events in tumor cells that induce or upregulate cell-surface expression of the ligands for these receptors, and the logic of how those pathways serve to identify malignant, or potentially malignant cells. How tumors often evade tumor suppression mediated by innate killer cells is another major subject of the review. We end with a discussion on some of the implications of the various findings with respect to possible therapeutic approaches.
    No preview · Article · Feb 2014 · Advances in Immunology
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    Alexandre Iannello · David H Raulet
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    ABSTRACT: We recently dissected how senescent tumors can trigger complementing signaling pathways that mobilize natural killer (NK) cells to eliminate malignant cells. In addition to cell-intrinsic effects on proliferation, senescence induces the production of chemokine (C-C motif) ligand 2 (CCL2), which recruits NK cells to mediate direct tumoricidal effects. Hence, senescence activates a cancer cell-extrinsic oncosuppression program.
    Preview · Article · Feb 2014 · OncoImmunology
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    Assaf Marcus · David H Raulet

    Preview · Article · Nov 2013 · Cytometry Part A
  • Alexandre Iannello · David H Raulet
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    ABSTRACT: Pathogenic and oncogenic insults result in the induction of intrinsic defense mechanisms such as cell-death pathways and senescence, and extrinsic pathways that mobilize immune responses to destroy unhealthy cells. Both protective mechanisms presumably evolved to limit the damage these insults could inflict on the host. After viral infection or malignant transformation, unhealthy cells can be directly sensed by natural killer (NK) and some T cells via the activating receptor NKG2D. All NK cells and subsets of T cells express NKG2D. The NKG2D/ligand system represents a major recognition mechanism for detection and elimination of unhealthy cells. Here we discuss different pathways, including stress pathways, that are responsible for cell-surface display of ligands for NKG2D, which are self-proteins that are minimally expressed by normal cells. We also discuss new results indicating that efficient elimination of tumor cells that display NKG2D ligands depends on the recruitment of NK cells and other immune cells to the tumor, which can be regulated by distinct mechanisms, including the p53-dependent production of chemokines by senescent tumors. The cooperative effect of pathways that induce the display of NKG2D ligands and distinct pathways that mobilize immune cells provides a higher degree of specificity to the NK cell response.
    No preview · Article · Oct 2013 · Cold Spring Harbor Symposia on Quantitative Biology
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    ABSTRACT: The induction of cellular senescence is an important mechanism by which p53 suppresses tumorigenesis. Using a mouse model of liver carcinoma, where cellular senescence is triggered in vivo by inducible p53 expression, we demonstrated that NK cells participate in the elimination of senescent tumors. The elimination of senescent tumor cells is dependent on NKG2D. Interestingly, p53 restoration neither increases ligand expression nor increases the sensitivity to lysis by NK cells. Instead, p53 restoration caused tumor cells to secrete various chemokines with the potential to recruit NK cells. Antibody-mediated neutralization of CCL2, but not CCL3, CCL4 or CCL5, prevented NK cell recruitment to the senescent tumors and reduced their elimination. Our findings suggest that elimination of senescent tumors by NK cells occurs as a result of the cooperation of signals associated with p53 expression or senescence, which regulate NK cell recruitment, and other signals that induce NKG2D ligand expression on tumor cells.
    Preview · Article · Sep 2013 · Journal of Experimental Medicine
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    ABSTRACT: The NKG2D activating receptor has been implicated in numerous autoimmune diseases. We tested the role of NKG2D in models of autoimmunity and inflammation using NKG2D knockout mice and antibody blockade experiments. The severity of experimental autoimmune encephalitis (EAE) was decreased in NKG2D-deficient mice when the disease was induced with a limiting antigen dose, but unchanged with an optimal antigen dose. Surprisingly, however, NKG2D deficiency had no detectable effect in several other models, including two models of type 1 diabetes, and a model of intestinal inflammation induced by poly(I:C). NKG2D antibody blockade in normal mice also failed to inhibit disease in the NOD diabetes model or the intestinal inflammation model. Published evidence using NKG2D knockout mice demonstrated a role for NKG2D in mouse models of atherosclerosis and liver inflammation, as well as in chronic obstructive pulmonary disease. Therefore, our results suggest that NKG2D plays selective roles in inflammatory diseases.
    No preview · Article · Sep 2013 · Clinical Immunology

Publication Stats

23k Citations
2,760.15 Total Impact Points

Institutions

  • 1992-2015
    • University of California, Berkeley
      • Department of Molecular and Cell Biology
      Berkeley, California, United States
  • 1979-2010
    • Massachusetts Institute of Technology
      • Department of Biology
      Cambridge, Massachusetts, United States
  • 2007
    • Pennsylvania State University
      • Department of Veterinary and Biomedical Sciences
      University Park, MD, United States
  • 2001
    • University of Freiburg
      • Department of Immunology
      Freiburg, Baden-Württemberg, Germany
  • 1988-1990
    • Whitehead Institute for Biomedical Research
      • Department of Biology
      Cambridge, Massachusetts, United States
  • 1989
    • National Cancer Institute (USA)
      Maryland, United States