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Cited by 414Immune Cell Function and InteractionTelomeres, Telomerase, and SenescenceCancer-related Molecular Pathways

p53-dependent chemokine production by senescent tumor cells supports NKG2D-dependent tumor elimination by natural killer cells

Open access
Iannello, Alexandre, Thompson, Thornton W., Ardolino, Michele, Lowe, Scott W., Raulet, David H.·2013·Journal of Experimental Medicine
DOI 10.1084/jem.20130783PMC PMC3782044
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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.

AI snapshot

Written from the paper’s full text.

TL;DR

p53 restoration in transplanted H-RasV12 liver tumor cells induces senescence and CCL2-dependent NK cell recruitment, leading to NKG2D-dependent elimination of senescent tumors. NKG2D ligands are already expressed before p53 induction; p53 acts mainly by recruiting and potentially activating NK cells rather than by increasing ligand expression or lysis sensitivity.

Key findings

  • In Rag2−/− mice, p53 induction caused tumor arrest and gradual disappearance; NK depletion or NKG2D deficiency/blockade delayed elimination similarly, showing NKG2D is essential for the rapid NK-dependent component.
  • p53 restoration did not significantly increase NKG2D ligand expression or in vitro NK lysis sensitivity; RAE-1ε was already high on tumor cells. In Rag2−/− mice, p53 restoration for 8 d reduced RAE-1ε on tumor cells, but not in Rag2−/−Klrk1−/− or NK-depleted mice.
  • p53 restoration increased tumor-infiltrating CD45+ cells nearly threefold and NK cells ∼20-fold, though NK cells remained only ∼2% of tumor infiltrates. CCL2 neutralization reduced NK recruitment (P < 0.01) and delayed tumor elimination (P < 0.001 at days 4, 6, and 8), whereas CCL3/4/5 neutralization did not affect NK recruitment.
  • p53 induced chemokines (CCL2, CCL4, CCL5 in vitro; CCL3, CXCL1, CXCL2 ex vivo) and cytokines (IL-15, IL12p40, IL-18, IL-1, IL-6). H-RasV12–transduced WT MEFs showed a fourfold increase in Ccl2 expression, much less in p53 KO MEFs, and CCL2 antibody blocked NK migration in transwell assays.

Methods

  • Subcutaneous mouse tumor model: 2 × 10^6 TRE_shp53 H-RasV12–transformed liver carcinoma cells injected into Rag2−/−, Rag2−/−Klrk1−/−, or NK-depleted mice; p53 induced with doxycycline; tumor volumes monitored by caliper.
  • In vitro and ex vivo analyses: liver tumor cells and WT or Trp53−/− MEFs transduced with H-RasV12; Q-RT-PCR, protein arrays, ELISA, flow cytometry, 51Cr-release NK cytotoxicity assays, and transwell NK migration assays.
  • Statistics: one- and two-way ANOVA with Bonferroni or Tukey tests, and unpaired two-tailed Student’s t tests; significance at P < 0.05.

Limitations

  • Stated: after NK depletion, tumors were still eliminated at later time points, suggesting other mechanisms such as neutrophils and/or macrophages; CCL2 neutralization delayed rejection significantly but less robustly than NK1.1 depletion; IFN-γ production by tumor NK cells was not detected; some chemokine up-regulation in CD45+ cells did not reach statistical significance.
  • Stated: further studies are needed to elucidate the senescence-dependent signals and cancer-associated pattern required to trigger immune surveillance.
  • Evident from the text: findings rely on a transplanted mouse liver tumor model and in vitro MEFs; the claim that tumor cells account for >85% of CCL2 transcripts is described as unpublished data, and human relevance is not directly tested.

Model-written summary. Check it against the paper before relying on it.

Integrity signals

Registry

Crossref · 10.1084/jem.20130783

Cites

52 of 52 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

0 of 48 cited sources checked · 0 supported · 0 flagged

  • Findingown data

    H-RasV12-transduced p53-expressing senescent MEFs strongly induce the migration of IL-2-activated NK cells in vitro.

    “H-RasV12–transduced p53-expressing senescent MEFs strongly induced the migration of IL-2–activated NK cells.”
    Quote in the paperSubstantial claim
  • Findingown data

    p53 induction does not significantly increase expression of NKG2D ligands in vitro or in vivo.

    “Cultivation of these cells in vitro with doxycycline for 7 d did not result in a significantly increased expression of any of the NKG2D ligands at either the protein level (as shown by staining with ligand-specific antibodies or by staining with NKG2D-Fc, which binds to all NKG2D ligands; Fig. 2 A) or mRNA level (Fig. 2 C).”
    • Also stated in: § p53 restoration is not necessary for expression of NKG2D ligands in the liver tumor cells · plain
      “Induction of p53 in vivo, in established tumors implanted in Rag2−/− Klrk1−/− recipients, also did not result in consistent or significantly increased expression of RAE-1ε (Fig. 2, B and D) or other NKG2D ligands (Fig. 2 A and not depicted), as shown by ex vivo analysis of tumor cell suspensions.”
    Quote in the paperSubstantial claim
  • Findingown data

    p53 restoration induces expression of multiple chemokines (CCL2, CCL3, CCL4, CCL5, CXCL1, CXCL2) in tumor cells in vitro and in vivo.

    “In vitro, restoration of p53 in transformed fetal liver cells resulted in significant increases in the mRNAs for several chemokines known to recruit immune cells, including CCL2, CCL4, and CCL5 (Fig. 6 A).”
    • Also stated in: § p53 restoration is associated with increased chemokine expression and NK cell recruitment · plain
      “A comparable analysis of ex vivo tumor samples from mice treated or not with doxycycline showed a similar induction of mRNAs for these chemokines and several others, including CCL3, CXCL1, and CXCL2 (Fig. 6 B).”
    • Also stated in: § p53 restoration is associated with increased chemokine expression and NK cell recruitment · plain
      “mRNAs for the CC-chemokines CCL2, CCL3, CCL4, and CCL5 and the CXC-chemokines CXCL1 and CXCL2 were found to be up-regulated in GFP+ tumor cells (Fig. 6 D) after p53 expression in vivo (Fig. 6 E).”
    Quote in the paperSubstantial claim
  • Findingown data

    Killing of tumor cells in vitro is largely NKG2D dependent.

    “The killing of the tumor cells in vitro, whether they expressed p53 or not, was nevertheless largely NKG2D dependent, as it was much reduced when the NK cells were derived from Klrk1−/− mice (Fig. 3 B).”
    • Also stated in: § p53 restoration is not necessary for expression of NKG2D ligands in the liver tumor cells · plain
      “blocking NKG2D with antibodies to prevent ligand recognition resulted in a significant decrease in the sensitivity of the tumor cells to killing by NK cells in vitro (Fig. 3 C).”
    Quote in the paperSubstantial claim
  • Findingown data

    Much less migration occurs with H-RasV12-transduced, p53 KO MEF.

    “Importantly, much less migration occurred with H-RasV12–transduced, p53 KO MEF.”
    Quote in the paperSubstantial claim
  • May combine two claims. 21
  • Classified as probably not a substantial claim. 26

  • May combine two claims.

    Findingown data

    H-RasV12 transduction induces Ccl2 mRNA and CCL2 protein in WT MEFs, but much less in p53 KO MEFs.

    “a fourfold increase in Ccl2 gene expression was observed in WT MEFs transduced with H-RasV12 (Fig. 7 B).”
    • Also stated in: § p53 restoration is associated with increased chemokine expression and NK cell recruitment · plain
      “In contrast, H-RasV12 transduction induced much less Ccl2 mRNA in p53 KO MEFs”
    • Also stated in: § p53 restoration is associated with increased chemokine expression and NK cell recruitment · plain
      “the amount of CCL2 protein secreted by H-RasV12–transduced WT MEFs was much higher than the amount secreted by H-RasV12–transduced p53 KO MEF.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Transformed fetal liver cells in the p53-off state express substantial amounts of RAE-1ε but do not express MULT1 or H60 family ligands.

    “Transformed fetal liver cells cultivated in vitro in the p53-off state expressed substantial amounts of one NKG2D ligand, RAE-1ε, but did not express MULT1 or H60 family ligands (Fig. 2 A).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    The reduction in RAE-1ε expression is not observed in Rag2−/−Klrk1−/− control recipients or in Rag2−/− mice depleted of NK cells.

    “The reduction was not observed in Rag2−/−Klrk1−/− control recipients, or in Rag2−/− mice that were depleted of NK cells (Fig. 4, A and B).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Some up-regulation of the same chemokines may also occur in CD45+ hematopoietic cells in the tumors, but the combined data from three experiments failed to reach statistical significance.

    “Some up-regulation of the same chemokines may also occur in CD45+ hematopoietic cells in the tumors (Fig. 6 E), but the combined data from three experiments failed to reach statistical significance.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    The accumulation of CD45+ cells in general, and of NK cells in particular, is not dependent on NKG2D, as it occurred equally in Rag2−/− and Rag2−/−Klrk1−/− mice.

    “the accumulation of CD45+ cells in general, and of NK cells in particular, was not dependent on NKG2D, as it occurred equally in Rag2−/− and Rag2−/−Klrk1−/− mice (Fig. 5, D and E).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    p53 restoration induces a progressive accumulation of immune (CD45+) cells in tumors, which is not observed in tumors that do not express p53.

    “p53 restoration induced a progressive accumulation of immune (CD45+) cells in the tumors, which was not observed in tumors that did not express p53 (Fig. 5 A).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    The percentage of CD45+ cells that are NK cells increases dramatically over the same time course in a p53-dependent fashion, and the percentage of NK cells among all cells in the tumor suspension increases strikingly.

    “the percentage of the CD45+ cells that were NK cells increased dramatically over the same time course in a p53-dependent fashion (Fig. 5 B)”
    • Also stated in: § p53 restoration is associated with increased chemokine expression and NK cell recruitment · plain
      “the percentage of NK cells among all cells in the tumor suspension increased strikingly as a result (Fig. 5 C).”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Findingown data

    The Ct values from Q-RT-PCR experiments suggested that the tumors produced greater amounts of CCL2 than of the other chemokines tested.

    “the Ct values from the Q-RT-PCR experiments suggested that the tumors produced greater amounts of CCL2 than of the other chemokines tested (unpublished data).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    IL-12, IL-15, and IL-1 are induced significantly in tumor cells.

    “Analysis of separated tumor cells and infiltrating CD45+ cells indicated that IL-12, IL-15, and IL-1, at least, were induced significantly in tumor cells”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    The delay in tumor elimination caused by CCL2 neutralization is significant though not as robust as the delay in mice treated with NK1.1 antibodies to deplete NK cells.

    “The delay in tumor elimination was significant though not as robust as the delay that occurred in mice treated with NK1.1 antibodies to deplete NK cells.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Neutralizing CCL2 causes a striking reduction in the recruitment of NK cells into the tumors, whereas neutralizing CCL3, CCL4, and CCL5 has no such effect.

    “Neutralizing CCL2 caused a striking reduction in the recruitment of NK cells into the tumors, whereas neutralizing CCL3, CCL4, and CCL5 had no such effect (Fig. 8, A and B).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    p53 induction in vitro and in vivo caused a strong induction of various important chemokines, as well as NK cell-activating interleukins including IL-12 and IL-15.

    “We observed a strong induction of various important chemokines, as well as NK cell–activating interleukins including IL-12 and IL-15 after p53 induction in vitro and in vivo.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationown data

    RAE-1 expression occurs without p53 induction in this model and p53 restoration and/or the senescent state do not further induce the expression of NKG2D ligands.

    “These data suggest that RAE-1 expression occurs without p53 induction in this model and that p53 restoration and/or the senescent state do not further induce the expression of NKG2D ligands.”
    • Also stated in: § Abstract · plain
      “RAE-1 expression is not induced by p53 expression because it is robust on the tumor cells even before p53 expression is induced.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationown data

    p53 expression facilitates NK cell-dependent tumor cell killing in vivo, resulting in the preferential elimination of tumor cells expressing high levels of RAE-1ε.

    “These data suggested that p53 expression facilitates NK cell-dependent tumor cell killing in vivo, resulting in the preferential elimination of tumor cells expressing high levels of the NK activating ligand RAE-1ε.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Interpretationcitation

    p53 may in some cases enhance NKG2D ligand expression.

    “Hence, p53 may in some cases enhance NKG2D ligand expression”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Knockout mice lacking NKG2D display an enhanced incidence and/or more rapid onset of cancers in certain mouse models of spontaneous cancer.

    “and that knockout mice lacking NKG2D display an enhanced incidence and/or more rapid onset of cancers in certain mouse models of spontaneous cancer (Guerra et al., 2008).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Guerra et al., 2008 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    Cytokines induced in senescent tumors may enhance NK cell activation within the tumors, aiding in tumor elimination.

    “Hence, cytokines induced in senescent tumors may enhance NK cell activation within the tumors, aiding in tumor elimination.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Interpretationcitation

    Direct evidence for the participation of these soluble factors was not provided.

    “but direct evidence for their participation was not provided.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Kang et al., 2011 source

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Premisecitation

    Senescence is a key mechanism by which p53 suppresses tumorigenesis.

    “It is believed that senescence is a key mechanism by which p53 suppresses tumorigenesis (Braig and Schmitt, 2006; Collado and Serrano, 2010).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites Braig and Schmitt, 2006 source

      Not checked in the free run.

    • cites Collado and Serrano, 2010 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationown data

    Induction of CCL2 expression as a result of p53 restoration substantially enhances NK cell recruitment to tumors, as well as NK cell-dependent elimination of tumor cells mediated by NKG2D interactions.

    “Collectively, the data support the conclusion that induction of CCL2 expression as a result of p53 restoration substantially enhanced NK cell recruitment to tumors, as well as NK cell–dependent elimination of tumor cells mediated by NKG2D interactions.”
    • Also stated in: § Abstract · plain
      “p53 induction regulates NK cell recruitment via CCL2, leading to NKG2D-dependent elimination of senescent tumors.”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim.

    Premisecitation

    H-RasV12 induces senescence in MEFs that express the wild-type form of p53.

    “These experiments were based on a previous study (Brady et al., 2011) showing that H-RasV12 induces senescence in MEFs that express the wild-type form of p53.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Brady et al., 2011 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    The presence of these soluble factors correlated with immune surveillance and infiltration by immune cells.

    “This study correlated the presence of these soluble factors with immune surveillance and infiltration by immune cells (Kang et al., 2011)”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Kang et al., 2011 source

      Not checked in the free run.

  • Classified as probably not a substantial claim. May combine two claims.

    Premisecitation

    Transplanted tumor cells expressing NKG2D ligands are rejected by NK cells and, in some cases, T cells.

    “Previous studies from our laboratory demonstrated that transplanted tumor cells expressing NKG2D ligands are rejected by NK cells and, in some cases, T cells (Diefenbach et al., 2000, 2001, 2003)”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites Diefenbach et al., 2000 source

      Not checked in the free run.

    • cites Diefenbach et al., 2001 source

      Not checked in the free run.

    • cites Diefenbach et al., 2003 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    NK cells can be rapidly recruited to sites of infection or inflammation due to expression of various chemokine receptors, including CCR2, CCR5, CXCR3, and CX3CR1.

    “NK cells can be rapidly recruited to sites of infection or inflammation due to expression of various chemokine receptors, including CCR2, CCR5, CXCR3, and CX3CR1 (Grégoire et al., 2007; Walzer and Vivier, 2011).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites Grégoire et al., 2007 source

      Not checked in the free run.

    • cites Walzer and Vivier, 2011

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Mouse livers harboring premalignant senescent hepatocytes showed an inflammatory reaction with large clusters of immune cells surrounding senescent hepatocytes.

    “another study showed that mouse livers harboring premalignant senescent hepatocytes showed an inflammatory reaction with large clusters of immune cells surrounding senescent hepatocytes (Kang et al., 2011).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Kang et al., 2011 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    NKG2D has been implicated in immune surveillance of tumors using transgenic models of spontaneous cancer as well as subcutaneous tumor transfer models.

    “NKG2D has been implicated in immune surveillance of tumors using transgenic models of spontaneous cancer as well as subcutaneous tumor transfer models (Cerwenka et al., 2001; Diefenbach et al., 2001; Guerra et al., 2008).”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites Cerwenka et al., 2001 source

      Not checked in the free run.

    • cites Diefenbach et al., 2001 source

      Not checked in the free run.

    • cites Guerra et al., 2008 source

      Not checked in the free run.

  • Classified as probably not a substantial claim. May combine two claims.

    Premisecitation

    CCR2 is the receptor for CCL2, whereas CCR5 is the receptor for CCL3, 4, and 5.

    “CCR2 is the receptor for CCL2, whereas CCR5 is the receptor for CCL3, 4, and 5.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites Grégoire et al., 2007 source

      Not checked in the free run.

    • cites Walzer and Vivier, 2011

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    When tumors lacking p53 expression were first established in T cell-deficient nude mice, subsequent induction of p53 with doxycycline resulted in the arrest of tumor growth and the gradual disappearance of the senescent tumors.

    “it was previously reported that when tumors lacking p53 expression were first established in T cell–deficient nude mice, subsequent induction of p53 with doxycycline resulted in the arrest of tumor growth and the gradual disappearance of the senescent tumors (Xue et al., 2007).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Xue et al., 2007 source

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Premisecitation

    A recent paper suggested that senescent tumors are targeted for elimination by NK cells and other innate effector cells.

    “A recent paper suggested that senescent tumors are targeted for elimination by NK cells and other innate effector cells (Xue et al., 2007).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Xue et al., 2007 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Pharmacological reactivation of p53 in specific cell lines can stimulate the expression of ULPB2, a ligand for human NKG2D.

    “In contrast, two studies reported that pharmacological reactivation of p53 in specific cell lines can stimulate the expression of ULPB2, a ligand for human NKG2D (Li et al., 2011; Textor et al., 2011).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites Li et al., 2011

      Not checked in the free run.

    • cites Textor et al., 2011 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Several cytokines (including CCL2) were directly secreted by the senescent hepatocytes.

    “Several cytokines (including CCL2) were directly secreted by the senescent hepatocytes.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Kang et al., 2011 source

      Not checked in the free run.

  • Classified as probably not a substantial claim. May combine two claims.

    Interpretationreasoning

    Enhanced recruitment and activation of NK cells resulting from p53 expression is important for rejection of tumor cells that express those ligands, as well as for tumors that express NKG2D ligands.

    “Thus, it is plausible that enhanced recruitment and activation of NK cells resulting from p53 expression is important for rejection of tumor cells that express those ligands, as well as for tumors that express NKG2D ligands.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: The mouse liver tumor cells and MEFs used are representative of human senescent tumor cells.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Different NK-activating receptors may be engaged and trigger cytotoxicity depending on the ligands expressed by the tumor cells.

    “Depending on the ligands expressed by the tumor cells studied, different NK-activating receptors may be engaged and trigger cytotoxicity (Vivier et al., 2011).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Vivier et al., 2011 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S2 (checkable).

    Interpretationreasoning

    Methods that restore these p53-mediated functions might be fruitful in enhancing NK cell-mediated tumor elimination.

    “Methods that restore these p53-mediated functions might therefore be fruitful in enhancing NK cell–mediated tumor elimination (Nardella et al., 2011).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Nardella et al., 2011 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductnone given

    The spontaneous release was in all cases <20% of the maximum release accomplished with detergent.

    “The spontaneous release was in all cases <20% of the maximum release accomplished with detergent.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Study design and conductnone given

    All animal procedures were performed according to the National Institutes of Health guidelines under protocols approved by the University of California Animal Care and Use Committee.

    “All animal procedures were performed according to the National Institutes of Health guidelines under protocols approved by the University of California Animal Care and Use Committee.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    CCL2 has been implicated in NK cell recruitment before but has not stood out as the major chemokine for recruiting these cells.

    “It has been implicated in NK cell recruitment before but has not stood out as the major chemokine for recruiting these cells (Grégoire et al., 2007).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Grégoire et al., 2007 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Interpretationreasoning

    p53 expression potentially boosted the activation state of the NK cells that reached the tumors.

    “and potentially the activation state of the NK cells that reached the tumors.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Interpretationreasoning

    p53 may also, in some cases, enhance rejection of tumors by NKG2D-independent recognition mechanisms.

    “Our findings that p53 acts in part by enhancing the recruitment and activation of NK cells has the additional implication that p53 may also, in some cases, enhance rejection of tumors by NKG2D-independent recognition mechanisms.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Interpretationown data

    In one case, tumor-infiltrating immune cells were probably the exclusive source of a cytokine (IL-6).

    “and in one case were probably the exclusive source of a cytokine (IL-6).”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductnone given

    The data are representative of at least three independent experiments.

    “The data are representative of at least three independent experiments.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    The Ccl2 gene may be directly transactivated by p53.

    “The Ccl2 gene, which may be directly transactivated by p53 (Hacke et al., 2010; Tang et al., 2012)”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites Hacke et al., 2010 source

      Not checked in the free run.

    • cites Tang et al., 2012 source

      Not checked in the free run.

42 of 42

  • The paper relies on this without support.

    In Rag2−/− mice, NK cells are the only known cells that express NKG2D.

    “the only known cells to express NKG2D in Rag2−/− mice”

  • The paper relies on this without support.

    The p53 restoration model in established liver tumors reflects the role of p53 and senescence in early tumorigenesis.

    “Our results suggest the importance of p53 expression and senescence in immune surveillance at the early stages of tumorigenesis before p53 is inactivated or lost due to mutation.”

  • The paper relies on this without support.

    The mouse liver tumor cells and MEFs used are representative of human senescent tumor cells.

    “In the case of the liver tumor cells studied here, for example, a high level of RAE-1 on the cells was insufficient to cause elimination of the tumor cells.”
3 of 3

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • Partial induction of senescence in tumours could eradicate or exacerbate the tumours.

    “The partial induction of senescence in tumours could eradicate or exacerbate the tumours 110,113”

    From Inside and out: the activities of senescence in cancer (2014) · cites this paper as [113]

  • NK cells that the SASP of senescent tumour cells attracts to the tumour may also destroy non-senescent tumour cells.

    “This study suggests that NK cells recruited to the tumour lesion by the SASP of senescent tumour cells may also kill non-senescent tumour cells.”

    From Inside and out: the activities of senescence in cancer (2014) · cites this paper as [113]

  • Recruitment and activation of T cells and natural killer cells at senescent cells in tumor microenvironment or altered macrophage polarization promote removal of senescent or damaged cells.

    “Recruitment and activation of T cells and natural killer cells at the location of senescent cells in the tumor microenvironment or altered polarization of macrophages promote the removal of senescent or damaged cells [29,358,359,360].”

    From Mechanisms and Regulation of Cellular Senescence (2021) · cites this paper as [359]

  • Secretion of inflammatory cytokines can elicit immune-mediated clearance of senescent tumour cells.

    “In addition to directly limiting replicative capacity, in this setting the secretion of inflammatory cytokines can elicit immune-mediated clearance of senescent tumour cells46.”

    From Stromal senescence establishes an immunosuppressive microenvironment that drives tumorigenesis (2016) · cites this paper as [46]

  • Pharmacological p53 reactivation establishes cellular senescence linked to an immunostimulatory SASP that recruits and activates NK cells, TEFF cells, and tumoricidal macrophages.

    “Additional immunostimulatory effects linked to pharmacological p53 reactivation in cancer cells include (but are not limited to) (1) downregulation of immunomodulatory cytokines linked to tumor progression, such as IL6 (Sahin et al., 2020); (2) upregulation of NKALs (Textor et al., 2011); and (3) establishment of cellular senescence linked to an immunostimulatory SASP that favors the recruitment”

    From Immunomodulation by targeted anticancer agents (2021) · cites this paper as Iannello et al., 2013

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

Each contradiction between two passages listed here was confirmed by an independent check.

  • Conflicting timing for the first chemokine-antibody injection

    Minor

    The Figure 8 caption says the first antibody injection occurred on day 0 of doxycycline treatment, whereas Materials and Methods says it occurred one day before treatment began.

1 of 1

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Authors
Iannello, A., Thompson, T. W., Ardolino, M., Lowe, S. W., & Raulet, D. H.
Affiliations
  • University of California, Berkeley (US)
  • Memorial Sloan Kettering Cancer Center (US)
Corresponding author
Raulet, David H.
ORCID
Venue
Journal of Experimental Medicine
Publisher
Rockefeller University Press
Published
2013-09-16
Volume
210
Issue
10
Pages
2057-2069
ISSN
  • 0022-1007 (ISSN-L)
  • 1540-9538
DOI
10.1084/jem.20130783
PMC
PMC3782044
OpenAlex
W2165259537
Semantic Scholar
b56924fe0dd62fff9e2b0fb41c390d9a533f57b4
Cited by
414
References
52
Citations by year
2026: 20 · 2025: 30 · 2024: 36 · 2023: 39 · 2022: 39 · 2021: 45 · 2020: 33 · 2019: 34 · 2018: 29 · 2017: 28 · 2016: 31 · 2015: 26 · 2014: 21 · 2013: 2
FWCI
14.74
Type
journal article
Language
en
Open access
Locations
  • The Journal of Experimental Medicine (publishedVersion)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by-nc-sa)
  • PubMed Central (publishedVersion, cc-by-nc-sa)
  • PubMed (publishedVersion)
  • eScholarship (California Digital Library) (submittedVersion)
Funders
  • Istituto Pasteur-Fondazione Cenci Bolognetti
  • National Institutes of Health
  • Canadian Institutes of Health Research
  • National Cancer Institute (P30CA008748)
  • National Institute of Allergy and Infectious Diseases (R01AI039642, T32AI100829)
Topics
  • Life Sciences › Immunology and Microbiology › Immunology › Immune Cell Function and Interaction
  • Health Sciences › Medicine › Physiology › Telomeres, Telomerase, and Senescence
  • Health Sciences › Medicine › Oncology › Cancer-related Molecular Pathways
Keywords
cellular senescence, p53, NKG2D, natural killer cells, chemokines, MCP-1, tumor eradication, NK cell recruitment, liver cancer
MeSH terms
Animals, Cytotoxicity, Immunologic, Killer Cells, Natural, Ligands, Neoplasms, Tumor Suppressor Protein p53, Cellular Senescence, Mice, Knockout, Chemokines, Chemokine CCL2, Cell Line, Tumor, Mice, NK Cell Lectin-Like Receptor Subfamily K

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