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ABSTRACT: Natural killer (NK) cells belong to the innate immune system and are potent cytolytic and cytokine-producing effector cells in response to tumor targets. NK cell based anti-tumor immunotherapy was so far mainly successful in patients with different types of leukemia. For instance, acute myeloid leukemia (AML) patients displayed a prolonged survival if transplanted with haploidentical stem cells giving rise to NK cells with a mismatch in inhibitory killer immunoglobulin receptors (KIRs) and recipients' HLA class I. Although promising results have been achieved with hematological tumors, solid tumors are in most cases poorly controlled by NK cells. Therapeutic protocols that aimed at improving NK cell responses in patients with solid malignancies succeeded in increasing NK cell numbers and functional responses of NK cells isolated from the patients' peripheral blood. However, in the majority of cases tumor progression and overall survival of patients were not significantly improved. There is increasing evidence that tumor-associated NK cells become gradually impaired during tumor progression compared to NK cells from peripheral blood and healthy tissues. Future protocols of NK cell based immunotherapy should integrate three important aspects to improve NK cell anti-tumor activity: facilitating NK cell migration to the tumor site, enhancing their infiltration into the tumor tissue and ensuring subsequent efficient activation in the tumor. This review summarizes the current knowledge of tumor-infiltrating NK cells and the influence of the tumor microenvironment on their phenotype and function.
Cancer Microenvironment 12/2012;
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ABSTRACT: Natural killer cell (NK cell)-based immunotherapy of cancer is hampered by the transient effector function of NK cells. Recently, mouse IL-12/15/18-preactivated NK cells were shown to persist with sustained effector function in vivo. Our study investigated the antitumor activity of such NK cells. A single injection of syngeneic IL-12/15/18-preactivated NK cells, but neither naive nor IL-15- or IL-2-pretreated NK cells, combined with irradiation substantially reduced growth of established mouse tumors. Radiation therapy (RT) was essential for the antitumor activity of transferred NK cells. IL-12/15/18-preactivated NK cells expressed high levels of IL-2Rα (CD25), and their rapid in vivo proliferation depended on IL-2 produced by CD4(+) T cells. IL-12/15/18-preactivated NK cells accumulated in the tumor tissue and persisted at high cell numbers with potent effector function that required the presence of CD4(+) T cells. RT greatly increased numbers and function of transferred NK cells. Human IL-12/15/18-preactivated NK cells also displayed sustained effector function in vitro. Our study provides a better understanding for the rational design of immunotherapies of cancer that incorporate NK cells. Moreover, our results reveal an essential role of CD4(+) T cell help for sustained antitumor activity by NK cells linking adaptive and innate immunity.
Journal of Experimental Medicine 12/2012; · 13.85 Impact Factor
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ABSTRACT: Myeloid-derived suppressor cells (MDSCs) represent a heterogeneous population of myeloid cells in cancer patients and tumor-bearing mice that potently inhibits T cell responses. During tumor progression, MDSCs accumulate in several organs, including the tumor tissue. So far, tumor-infiltrating MDSC subpopulations remain poorly explored. In this study, we performed global gene expression profiling of mouse tumor-infiltrating granulocytic and monocytic (MO-MDSC) subsets compared with MDSCs from peripheral blood. RMA-S lymphoma-infiltrating MO-MDSCs not only produced high levels of NO and arginase-1, but also greatly increased levels of chemokines comprising the CCR5 ligands CCL3, CCL4, and CCL5. MO-MDSCs isolated from B16 melanoma and from skin tumor-bearing ret transgenic mice also expressed high levels of CCL3, CCL4, and CCL5. Expression of CCR5 was preferentially detected on regulatory T cells (Tregs). Accordingly, tumor-infiltrating MO-MDSCs directly attracted high numbers of Tregs via CCR5 in vitro. Intratumoral injection of CCL4 or CCL5 increased tumor-infiltrating Tregs, and deficiency of CCR5 led to their profound decrease. Moreover, in CCR5-deficient mice, RMA-S and B16 tumor growth was delayed emphasizing the importance of CCR5 in the control of antitumor immune responses. Overall, our data demonstrate that chemokines secreted by tumor-infiltrating MO-MDSCs recruit high numbers of Tregs revealing a novel suppressive role of MDSCs with potential clinical implications for the development of cancer immunotherapies.
The Journal of Immunology 11/2012; · 5.79 Impact Factor
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Manfred Lehner,
Gabriel Götz,
Julia Proff,
Niels Schaft,
Jan Dörrie,
Florian Full,
Armin Ensser,
Yves A Muller, Adelheid Cerwenka,
Hinrich Abken,
Ornella Parolini,
Peter F Ambros,
Heinrich Kovar,
Wolfgang Holter
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ABSTRACT: We explored the possibility to target Ewing's sarcoma family of tumors (ESFT) by redirecting T cells. To this aim, we considered NKG2D-ligands (NKG2D-Ls) as possible target antigens. Detailed analysis of the expression of MICA, MICB, ULBP-1, -2, and -3 in fourteen ESFT cell lines revealed consistent expression of at least one NKG2D-L. Thus, for redirecting T cells, we fused a CD3ζ/CD28-derived signaling domain to the ectodomain of NKG2D, however, opposite transmembrane orientation of this signaling domain and NKG2D required inverse orientation fusion of either of them. We hypothesized that the particularly located C-terminus of the NKG2D ectodomain should allow reengineering of the membrane anchoring from a native N-terminal to an artificial C-terminal linkage. Indeed, the resulting chimeric NKG2D receptor (chNKG2D) was functional and efficiently mediated ESFT cell death triggered by activated T cells. Notably, ESFT cells with even low NKG2D-L expression were killed by CD8(pos) and also CD4(pos) cells. Both, mRNA transfection and lentiviral transduction resulted in high level surface expression of chNKG2D. However, upon target-cell recognition receptor surface levels were maintained by tranfected RNA only during the first couple of hours after transfection. Later, target-cell contact resulted in strong and irreversible receptor down-modulation, whereas lentivirally mediated expression of chNKG2D remained constant under these conditions. Together, our study defines NKG2D-Ls as targets for a CAR-mediated T cell based immunotherapy of ESFT. A comparison of two different methods of gene transfer reveals strong differences in the susceptibility to ligand-induced receptor down-modulation with possible implications for the applicability of RNA transfection.
PLoS ONE 01/2012; 7(2):e31210. · 4.09 Impact Factor
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Benyamin Rosental,
Michael Brusilovsky,
Uzi Hadad,
Dafna Oz,
Michael Y Appel,
Fabian Afergan,
Rami Yossef,
Lior Ann Rosenberg,
Amir Aharoni, Adelheid Cerwenka,
Kerry S Campbell,
Alex Braiman,
Angel Porgador
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ABSTRACT: NK cells play an important role in the early immune response to cancer. The NKp44 activating receptor is the only natural cytotoxicity receptor that is expressed exclusively by primate NK cells, yet its cellular ligands remain largely unknown. Proliferating cell nuclear Ag (PCNA) is overexpressed in cancer cells. In this study, we show that the NKp44 receptor recognizes PCNA. Their interaction inhibits NK cell function through NKp44/ITIM. The physical interaction of NKp44 and PCNA is enabled by recruitment of target cell PCNA to the NK immunological synapse. We demonstrate that PCNA promotes cancer survival by immune evasion through inhibition of NKp44-mediated NK cell attack.
The Journal of Immunology 12/2011; 187(11):5693-702. · 5.79 Impact Factor
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Mostafa Jarahian,
Manuela Fiedler,
André Cohnen,
Dominik Djandji,
Günter J Hämmerling,
Cornelius Gati, Adelheid Cerwenka,
Peter C Turner,
Richard W Moyer,
Carsten Watzl,
Hartmut Hengel,
Frank Momburg
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ABSTRACT: Natural killer (NK) cells are an important element in the immune defense against the orthopox family members vaccinia virus (VV) and ectromelia virus (ECTV). NK cells are regulated through inhibitory and activating signaling receptors, the latter involving NKG2D and the natural cytotoxicity receptors (NCR), NKp46, NKp44 and NKp30. Here we report that VV infection results in an upregulation of ligand structures for NKp30 and NKp46 on infected cells, whereas the binding of NKp44 and NKG2D was not significantly affected. Likewise, infection with ectromelia virus (ECTV), the mousepox agent, enhanced binding of NKp30 and, to a lesser extent, NKp46. The hemagglutinin (HA) molecules from VV and ECTV, which are known virulence factors, were identified as novel ligands for NKp30 and NKp46. Using NK cells with selectively silenced NCR expression and NCR-CD3ζ reporter cells, we observed that HA present on the surface of VV-infected cells, or in the form of recombinant soluble protein, was able to block NKp30-triggered activation, whereas it stimulated the activation through NKp46. The net effect of this complex influence on NK cell activity resulted in a decreased NK lysis susceptibility of infected cells at late time points of VV infection when HA was expression was pronounced. We conclude that poxviral HA represents a conserved ligand of NCR, exerting a novel immune escape mechanism through its blocking effect on NKp30-mediated activation at a late stage of infection.
PLoS Pathogens 08/2011; 7(8):e1002195. · 9.13 Impact Factor
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ABSTRACT: Natural killer (NK) cells are immune cells sensing and eliminating foreign, stressed, transformed, and senescent cells through specialized surface receptors, such as NKG2D, that interacts with several virus- or stress-inducible ligands, including ULBP1 and -2, which are expressed on target cell surfaces. For example, induction of DNA damage or cellular senescence pathways in tumor cells led to upregulation of NKG2D ligands that activate NK cells. Although, both pathways activate p53, the relationship of p53 activation to upregulation of NKG2D ligands has not been addressed. In this study, we report that induction of wild-type p53, but not mutant p53, strongly upregulated mRNA and cell surface expression of ULBP1 and -2, whereas expression of other NK cell ligands was not affected. We defined intronic p53-responsive elements in these two novel p53 target genes. Coculture of wild-type p53-induced human tumor cells with primary human NK cells enhanced NKG2D-dependent degranulation and IFN-γ production by NK cells. Accordingly, treatment of certain wild-type p53-expressing tumor cell lines with the p53-reactivating small molecular compound RITA resulted in upregulation of ULBP2 mRNA and cell surface protein expression. Taken together, our findings define the involvement of p53 in the regulation of specific NKG2D ligands that enhance NK cell-mediated target recognition. One implication of our work is that activating p53 after adoptive transfer of NK cells might constitute an effective combinatorial strategy of NK cell-based immunochemotherapy in cancers in which wild-type p53 function is preserved.
Cancer Research 07/2011; 71(18):5998-6009. · 7.86 Impact Factor
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Tereza Ormsby,
Eva Schlecker,
Janina Ferdin,
Anja Sibylle Tessarz,
Pavla Angelisová,
Afitap Derya Köprülü,
Michael Borte,
Klaus Warnatz,
Ilka Schulze,
Wilfried Ellmeier,
Václav Horejsí, Adelheid Cerwenka
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ABSTRACT: The triggering receptor expressed on myeloid cells 1 (TREM-1) has been implicated in the production of proinflammatory cytokines and chemokines during bacterial infection and sepsis. For downstream signal transduction, TREM-1 is coupled to the ITAM-containing adaptor DAP12. Here, we demonstrate that Bruton tyrosine kinase (Btk), a member of the Tec kinases, becomes phosphorylated upon TREM-1 triggering. In U937-derived cell lines, in which expression of Btk was diminished by shRNA-mediated knockdown, phosphorylation of Erk1/2 and PLCγ1 and Ca²⁺ mobilization were reduced after TREM-1 stimulation. Importantly, TREM-1-induced production of the pro-inflammatory cytokines, TNF-α and IL-8, and up-regulation of activation/differentiation cell surface markers were impaired in Btk knockdown cells. Similar results were obtained upon TREM-1 stimulation of BMDCs of Btk(-/-) mice. The analysis of cells containing Btk mutants revealed that intact membrane localization and a functional kinase domain were required for TREM-1-mediated signaling. Finally, after TREM-1 engagement, TNF-α production by PBMCs was reduced in the majority of patients suffering from X-linked agammaglobulinemia (XLA), a rare hereditary disease caused by mutations in the BTK gene. In conclusion, our data identify Btk as a positive regulator in the ITAM-mediated TREM-1/DAP12 pathway and suggest its implication in inflammatory processes.
Blood 06/2011; 118(4):936-45. · 9.90 Impact Factor
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ABSTRACT: NK cell recognition of tumor cells is mediated by a delicate balance of signals received by MHC class I-binding inhibitory NK cell receptors and activating NK cell receptors, which mainly bind to virus-, stress- or tumor-induced ligands. In addition, adhesion molecules such as the intercellular adhesion molecule-1 (ICAM-1) and its receptors, the lymphocyte function-associated antigen-1 (LFA-1) and Mac-1, are crucial for immune synapse formation and NK cell-mediated killing. In this study, we show that expression of the adhesion molecule ICAM-1 was rapidly induced by E6 and -E7 oncoproteins of HPV16, -18, -5 and -8, but not of HPV38 and -6 in primary human keratinocytes after retroviral transduction. ICAM-1 was upregulated in E6E7-expressing keratinocytes both at mRNA and protein levels. The observed ICAM-1 upregulation in HPV16-E6E7-expressing keratinocytes was partially dependent on activation of the NF-κB pathway. Importantly, the upregulated ICAM-1 expression in HPV16-E6E7-expressing keratinocytes led to enhanced conjugate formation with NK cells. We previously showed that HPV16-positive cervical carcinomas frequently express low levels of inhibitory NK cell ligands and high levels of activating NK cell ligands. Moreover, levels of the adhesion molecule ICAM-1 are enhanced by HPV16-E6/E7. Therefore, strategies that aim at harnessing NK cells might be beneficial for the treatment of cervical carcinoma.
International Journal of Cancer 03/2011; 128(5):1104-13. · 5.44 Impact Factor
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Arthur Liesz,
Wei Zhou,
Éva Mracskó,
Simone Karcher,
Henrike Bauer,
Sönke Schwarting,
Li Sun,
Dunja Bruder,
Sabine Stegemann, Adelheid Cerwenka,
Clemens Sommer,
Alexander H Dalpke,
Roland Veltkamp
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ABSTRACT: T lymphocytes are increasingly recognized as key modulators of detrimental inflammatory cascades in acute ischaemic stroke, but the potential of T cell-targeted therapy in brain ischaemia is largely unexplored. Here, we characterize the effect of inhibiting leukocyte very late antigen-4 and endothelial vascular cell adhesion molecule-1-mediated brain invasion-currently the most effective strategy in primary neuroinflammatory brain disease in murine ischaemic stroke models. Very late antigen-4 blockade by monoclonal antibodies improved outcome in models of moderate stroke lesions by inhibiting cerebral leukocyte invasion and neurotoxic cytokine production without increasing the susceptibility to bacterial infections. Gene silencing of the endothelial very late antigen-4 counterpart vascular cell adhesion molecule-1 by in vivo small interfering RNA injection resulted in an equally potent reduction of infarct volume and post-ischaemic neuroinflammation. Furthermore, very late antigen-4-inhibition effectively reduced the post-ischaemic vascular cell adhesion molecule-1 upregulation, suggesting an additional cross-signalling between invading leukocytes and the cerebral endothelium. Dissecting the specific impact of leukocyte subpopulations showed that invading T cells, via their humoral secretion (interferon-γ) and immediate cytotoxic mechanisms (perforin), were the principal pathways for delayed post-ischaemic tissue injury. Thus, targeting T lymphocyte-migration represents a promising therapeutic approach for ischaemic stroke.
Brain 03/2011; 134(Pt 3):704-20. · 9.46 Impact Factor
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ABSTRACT: A plasmid encoding the Hemagglutinin-Neuraminidase (HN) protein of Newcastle Disease Virus (pHN) was tested for its capacity to stimulate innate anti-tumor activity in tumor-bearing mice. We observed that application of the pHN plasmid at the ear pinna site (i.e.) of mice induces higher levels of systemic interferon-α and reduced tumor growth in the prophylactic mammary carcinoma DA3 tumor model in comparison to application of a control plasmid not encoding the HN protein. Analysis of the tumor microenvironment revealed a significant increase in NK cell infiltration and decrease in infiltration of CD11b(+)Gr-1(high) myeloid cells bearing the myeloid-derived suppressor cell (MDSC) phenotype after vaccination with the pHN DNA compared to a control DNA. Finally, innate immunity and partially type I IFN responses were proved important for the reduction of s.c. RMA-S tumor growth after pHN vaccination, as shown with the use of RAG2(-/-) and RAG2(-/-)IFNAR1(-/-) mice. These data demonstrate that triggering innate immunity by pHN application at the ear pinna of mice modulates the immune cell compartment in the tumor microenvironment and reduces tumor growth. This highlights thus the potential adjuvant activity of the HN gene in tumor therapy.
Vaccine 02/2011; 29(6):1185-93. · 3.77 Impact Factor
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ABSTRACT: Natural killer (NK) cells play an important role in the innate immune response against cancer, in particular in the elimination of tumor metastases and small tumors. NK cell-mediated control of large solid tumors is usually not efficient, although tumors often express high amounts of activating ligands and low levels of inhibitory ligands, such as MHC class I. Thus, we assume that these tumors might be good targets for NK cell-mediated attack. In vitro, NK cells directly kill tumor cells and release soluble factors that affect both innate and adaptive immune responses. To date, in vivo NK cell activation during tumor progression, the influence of the tumor microenvironment on NK cells, and the mechanisms that interfere with their effector function in cancer patients are not completely understood. This review summarizes our current knowledge of NK cells in solid tumors. We will discuss the impact of novel insights into NK cell responses against tumors on the design of NK cell-based therapies.
Journal of Innate Immunity 01/2011; 3(4):355-64. · 4.21 Impact Factor
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ABSTRACT: Strategies of manipulating immunosuppressive regulatory T cells (Treg) in cancer patients are currently evaluated in clinical trials. Treg suppress immune responses of tumor-specific T cells; yet, relatively little is known about the impact of Treg on innate immune cells in tumor models in vivo. Many tumors lose expression of MHC class I. Therefore, our study aimed at defining strategies to strengthen immune responses against a high tumor burden of the MHC class I-deficient mouse lymphoma RMA-S. We demonstrate that Treg depletion in mice led to tumor rejection that was dependent on T cells, NK cells and IFN-gamma. In the absence of Treg elevated levels of IFN-gamma were produced by tumor-infiltrating T cells and NK cells. Tumor rejection observed in the absence of Treg correlated with a substantial IFN-gamma-dependent increase in the numbers of tumor-infiltrating leukocytes. The most abundant cell population in the tumors was macrophages. Tumor-infiltrating macrophages from Treg-depleted mice expressed increased amounts of MHC class II, produced highly enhanced levels of pro-inflammatory cytokines and inhibited tumor cell proliferation. It was reported that tumor-infiltrating macrophages have multi-faceted functions promoting or counteracting tumor growth. In our study, high numbers of macrophages infiltrating RMA-S tumors in the absence of Treg correlated with tumor rejection suggesting that macrophages are additional targets for Treg-mediated immune suppression in cancer.
International Journal of Cancer 12/2009; 127(5):1131-40. · 5.44 Impact Factor
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ABSTRACT: Triggering receptor expressed on myeloid cells 1 (TREM-1) is an activating receptor involved in inflammatory diseases and septic shock. The TREM-1 ligand(s) (TREM-1L) have not yet been identified. In this study, we performed a detailed analysis of the expression of mouse TREM-1 and its ligand(s). Our results demonstrate that TREM-1 is expressed on bone-marrow-derived dendritic cells (BMDC). On bone-marrow-derived macrophages (BMM) its expression is induced in vitro after stimulation by granulocyte-macrophage colony-stimulating factor, interleukin-3 or by myeloid differentiation primary response gene 88 (MyD88)-dependent Toll-like receptor (TLR) ligands. Under steady-state conditions mouse TREM-1 is detectable on a Gr-1(-) F4/80(+) monocyte subpopulation bearing markers of resident monocytes, but not on Gr-1(+) F4/80(+) inflammatory monocytes. During lipopolysaccharide (LPS)-induced endotoxaemia TREM-1 was also up-regulated on inflammatory Gr-1(+) F4/80(+) cells in vivo. In tumour-bearing mice, TREM-1 was up-regulated on Gr-1(+) F4/80(+) monocytes, which phenotypically and functionally resembled mononuclear myeloid-derived suppressor cells. Using a soluble TREM-1 fusion protein, we demonstrate that after intravenous injection of LPS TREM-1L was induced on Gr-1(+) granulocytes and monocytes but not on other cell populations in peripheral blood. This up-regulation on granulocytes was directly mediated by TLR ligands and required the adapter protein MyD88. In contrast to human, mouse platelets expressed TREM-1L neither under steady-state conditions nor after LPS injection in vivo. Our study reveals differential regulation of TREM-1 expression on mouse monocyte subpopulations and improves our understanding of the biological role of TREM-1 during disease.
Immunology 11/2009; 128(2):185-95. · 3.32 Impact Factor
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ABSTRACT: The avian paramyxovirus Newcastle disease virus (NDV) selectively replicates in tumor cells and is known to stimulate T-cell-, macrophage-, and NK cell-mediated responses. The mechanisms of NK cell activation by NDV are poorly understood so far. We studied the expression of ligand structures for activating NK cell receptors on NDV-infected tumor cells. Upon infection with the nonlytic NDV strain Ulster and the lytic strain MTH-68/H, human carcinoma and melanoma cells showed enhanced expression of ligands for the natural cytotoxicity receptors NKp44 and NKp46, but not NKp30. Ligands for the activating receptor NKG2D were partially downregulated. Soluble NKp44-Fc and NKp46-Fc, but not NKp30-Fc, chimeric proteins bound specifically to NDV-infected tumor cells and to NDV particle-coated plates. Hemagglutinin-neuraminidase (HN) of the virus serves as a ligand structure for NKp44 and NKp46, as indicated by the blockade of binding to NDV-infected cells and viral particles in the presence of anti-HN antibodies and by binding to cells transfected with HN cDNA. Consistent with the recognition of sialic acid moieties by the viral lectin HN, the binding of NKp44-Fc and NKp46-Fc was lost after desialylation. NKp44- and NKp46-CD3zeta lacZ-inducible reporter cells were activated by NDV-infected cells. NDV-infected tumor cells stimulated NK cells to produce increased amounts of the effector lymphokines gamma interferon and tumor necrosis factor alpha. Primary NK cells and the NK line NK-92 lysed NDV-infected tumor cells with enhanced efficiency, an effect that was eliminated by the treatment of target cells with the neuraminidase inhibitor Neu5Ac2en. These results suggest that direct activation of NK cells contributes to the antitumor effects of NDV.
Journal of Virology 07/2009; 83(16):8108-21. · 5.40 Impact Factor
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Moshe Elkabets,
Yakov Krelin,
Shahar Dotan, Adelheid Cerwenka,
Angel Porgador,
Rachel G Lichtenstein,
Malka R White,
Margot Zoller,
Yoichizo Iwakura,
Charles A Dinarello,
Elena Voronov,
Ron N Apte
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ABSTRACT: Using IL-1/IL-1Ra knockout BALB/c mice, we showed that 3-methylcholatrene (3-MCA)-induced carcinogenesis is dependent on IL-1beta-induced inflammatory responses. Patterns of local inflammation and tumorigenicity were similar in wild-type (WT) and IL-1alpha(-/-) mice, while in IL-1beta(-/-) mice, tumorigenicity was attenuated and in IL-1Ra(-/-) mice accentuated. 3-MCA-induced fibrosarcoma cell lines from WT mice developed into progressive tumors in WT mice, while surprisingly, lines from IL-1alpha(-/-) mice formed tumors only in immunocompromized mice. 3-MCA-induced fibrosarcoma cell lines from IL-1alpha(-/-) mice, compared with lines from WT mice, manifested higher expression levels of "global" surface molecules related to Ag presentation and interactions with immune surveillance cells (MHC class I, B7.1, B7.2, L-selectin, and NKG2D ligands) and were eradicated mainly by CD4(+)- and CD8(+)-dependent T cell responses. Concomitantly, at the injection site of 3-MCA-induced fibrosarcoma cells derived from IL-1alpha(-/-) mice, a leukocyte infiltrate, subsequently replaced by a scar-like tissue, was observed. Immune aberrations in NK cell maturation, antitumor specific immunity and killing capacity of effector cells were observed in IL-1alpha(-/-) mice, in contrast to WT mice. Thus, we demonstrate in this study the significance of host-derived IL-1alpha in cancer immunoediting, by affecting innate and specific immunosurveillance mechanisms. Overall, the results presented in this study, together with our previous studies, attest to differential involvement of IL-1alpha and IL-1beta in tumorigenesis; host-derived IL-1beta mainly controls inflammation, while concomitantly, IL-1alpha controls immunosurveillance of the arising malignant cells. Elucidation of the involvement of the IL-1 molecules in the malignant process will hopefully lead to the development of novel approaches for chemoprevention and immunotherapy.
The Journal of Immunology 05/2009; 182(8):4874-81. · 5.79 Impact Factor
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Adelheid Cerwenka
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ABSTRACT: The NK cell-activating receptor NKG2D plays a prominent role in antitumor immune responses. Expression of the multiple NKG2D ligands must be tightly controlled to guarantee that NK cells attack tumors but not healthy cells. New data reveal a novel mechanism of posttranslational regulation of the mouse NKG2D ligand MULT1, in which MULT1 is ubiquitinated and degraded in healthy cells. In response to UV stress or heat shock, ubiquitination of MULT1 decreases and cell surface expression increases. Thus, targeting the ubiquitination machinery in cancer cells might increase the susceptibility of tumors to NK cell-mediated killing.
Journal of Experimental Medicine 03/2009; 206(2):265-8. · 13.85 Impact Factor
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ABSTRACT: Several studies have correlated high numbers of tumor-infiltrating natural killer (NK) cells with a good prognosis for cancer patients. Our study aimed at identifying factors controlling intratumoral NK cell accumulation in s.c. injected NK cell sensitive tumor models and at studying their effect on survival time of recipient mice. We observed that fewer NK cells infiltrated the tumors in IFN-gamma receptor knockout (IFN-gammaR(-/-)) mice compared with wild-type controls that correlated with decreased survival rate. Exogenous application of IFN-gamma in the tumor augmented levels of ligands of the chemokine receptor CXCR3, increased NK cell accumulation, and prolonged survival. Furthermore, our data show that CD27(high) NK cells, which under steady-state conditions express CXCR3, preferentially accumulated in the tumor tissue. Accordingly, significantly lower numbers of tumor-infiltrating NK cells were detected in CXCR3(-/-) mice, and the capacity of adoptively transferred CXCR3(-/-) NK cells to accumulate in the tumor was severely impaired. Finally, exogenous application of the CXCR3 ligand CXCL10 in the tumor or ectopic expression of CXCL10 by tumor cells increased the numbers of NK cells in the tumors and prolonged NK cell-dependent survival. Our results identify IFN-gamma and the expression of CXCR3 on NK cells as prerequisites for NK cell infiltration into tumors. Exploiting strategies to augment NK cell accumulation in the tumor might lead to the development of effective antitumor therapies.
Cancer Research 11/2008; 68(20):8437-45. · 7.86 Impact Factor
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Nicole Schwinn,
Daria Vokhminova,
Antje Sucker,
Sonja Textor,
Sandra Striegel,
Iris Moll,
Norman Nausch,
Jochen Tuettenberg,
Alexander Steinle, Adelheid Cerwenka,
Dirk Schadendorf,
Annette Paschen
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ABSTRACT: NKG2D operates as an activating receptor on natural killer (NK) cells and costimulates the effector function of alphabeta CD8(+) T cells. Ligands of NKG2D, the MHC class I chain-related (MIC) and UL16 binding protein (ULBP) molecules, are expressed on a variety of human tumors, including melanoma. Recent studies in mice demonstrated that NKG2D mediates tumor immune surveillance, suggesting that antitumor immunity in humans could be enhanced by therapeutic manipulation of NKG2D ligand (NKG2DL) expression. However, signals and mechanisms regulating NKG2DL expression still need to be elucidated. Here, we asked whether the proinflammatory cytokine Interferon-gamma (IFN-gamma) affects NKG2DL expression in melanoma. Cell lines, established from MHC class I-negative and -positive melanoma metastases, predominantly expressed MICA and ULBP2 molecules on their surface. Upon IFN-gamma treatment, expression of MICA, in some cases, also of ULBP2 decreased. Besides melanoma, this observation was made also for glioma cells. Down-regulation of NKG2DL surface expression was dependent on the cytokine dose and the duration of treatment, but was neither due to an intracellular retention of the molecules nor to an increased shedding of ligands from the tumor cell surface. Instead, quantitative RT-PCR revealed a decrease of MICA-specific mRNA levels upon IFN-gamma treatment and siRNA experiments pointed to an involvement of STAT-1 in this process. Importantly, IFN-gamma-treated MHC class I-negative melanoma cells were less susceptible to NKG2D-mediated NK cell cytotoxicity. Our study suggests that IFN-gamma, by down-regulating ligand expression, might facilitate escape of MHC class I-negative melanoma cells from NKG2D-mediated killing by NK cells.
International Journal of Cancer 11/2008; 124(7):1594-604. · 5.44 Impact Factor
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Nicole Schwinn,
Daria Vokhminova,
Antje Sucker,
Sonja Textor,
Sandra Striegel,
Iris Moll,
Norman Nausch,
Jochen Tuettenberg,
Alexander Steinle, Adelheid Cerwenka,
Dirk Schadendorf,
Annette Paschen
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ABSTRACT: NKG2D operates as an activating receptor on natural killer (NK) cells and costimulates the effector function of β CD8+ T cells. Ligands of NKG2D, the MHC class I chain-related (MIC) and UL16 binding protein (ULBP) molecules, are expressed on a variety of human tumors, including melanoma. Recent studies in mice demonstrated that NKG2D mediates tumor immune surveillance, suggesting that antitumor immunity in humans could be enhanced by therapeutic manipulation of NKG2D ligand (NKG2DL) expression. However, signals and mechanisms regulating NKG2DL expression still need to be elucidated. Here, we asked whether the proinflammatory cytokine Interferon- (IFN-) affects NKG2DL expression in melanoma. Cell lines, established from MHC class I-negative and -positive melanoma metastases, predominantly expressed MICA and ULBP2 molecules on their surface. Upon IFN- treatment, expression of MICA, in some cases, also of ULBP2 decreased. Besides melanoma, this observation was made also for glioma cells. Down-regulation of NKG2DL surface expression was dependent on the cytokine dose and the duration of treatment, but was neither due to an intracellular retention of the molecules nor to an increased shedding of ligands from the tumor cell surface. Instead, quantitative RT-PCR revealed a decrease of MICA-specific mRNA levels upon IFN- treatment and siRNA experiments pointed to an involvement of STAT-1 in this process. Importantly, IFN--treated MHC class I-negative melanoma cells were less susceptible to NKG2D-mediated NK cell cytotoxicity. Our study suggests that IFN-, by down-regulating ligand expression, might facilitate escape of MHC class I-negative melanoma cells from NKG2D-mediated killing by NK cells. © 2008 Wiley-Liss, Inc.
International Journal of Cancer 10/2008; 124(7):1594 - 1604. · 5.44 Impact Factor
