Table Of ContentAUTHOR'SVIEW
OncoImmunology1:3,397 –398;May/June2012; G2012LandesBioscience
Immune surveillance of pre-cancerous senescent
hepatocytes limits hepatocellular carcinoma
development
Tetyana Yevsa,1,2 Tae-Won Kang1 and Lars Zender1,2,*
1HelmholtzCentreforInfectionResearch;Braunschweig,Germany;2HannoverMedicalSchool;DepartmentofGastroenterology,HepatologyandEndocrinology;
Hannover,Germany
Keywords: senescence, surveillance, hepatocellular, carcinoma, cancer, immune, premalignant
Here we discuss a recently published study from our group on how a continuous CD4 T-cell dependent immune
clearanceof premalignantsenescent cells, designated “senescence surveillance,”restricts livercancer development.
Upontheaberrantactivationofoncogenes cells, time course analyses revealed a CD4 T-cells in mice harboring senescent
cells can either undergo apoptosis or progressive loss of NrasG12V expressing NrasG12V expressing hepatocytes but not
cellular senescence, a state of stable cell senescent cells within two months after in NrasG12V-transduced p19Arf knockout
cycle arrest.1 Like apoptosis, cellular stable intrahepatic delivery of oncogenic mice, in which induction of the cellular
senescence was shown to also represent NrasG12V. Importantly, all analyses were senescence program is genetically dis-
an important failsafe mechanism against paralleled using a NrasG12V effector loop abled. Collectively, our data showed that
tumor development in vivo (reviewed mutant (NrasG12V/D38A) incapable of signal- oncogene induced senescence (OIS) plays
in ref. 2). While cellular senescence so ingtodownstreampathwaysandtherefore an important role in the induction of
far has been regarded a solely cell intrinsic for senescence induction. Importantly, specific immune responses against anti-
mechanism of tumor suppression, i.e., NrasG12V/D38Aexpressinghepatocytescould gens expressed in pre-cancerous cells.
suppressing tumor development through be detected long-term after intrahepatic Further mechanistic studies characterized
the induction of a stable cell cycle arrest, delivery, thus ruling out immune res- the observed CD4 T-cell response as a
recent data from our laboratory suggest ponses against overexpressed Nras peptide Th1 type response and we found that
that the cellular senescence program also per se. To address the significance of CD4 T-cells depended on monocytes and
plays a crucial role in the induction of the observed immune cell populations for freshly replenished macrophages to effi-
immune responses against pre-cancerous the clearance of senescent cells, we took ciently kill senescent hepatocytes (Fig.1).
cells.3Tomimicaberrantoncogeneactiva- a genetic approach: NrasG12V expressing Interestingly, liver resident macrophages
tion, which can occur in hepatocytes of transposable elements were intrahepati- (Kupffer cells) were found not to be
chronically damaged human livers, we cally delivered into mice harboring gene- involved in the killing of NrasG12V
stably delivered oncogenic NrasG12V into tically defined immune defects and the expressing senescent hepatocytes.
mouse livers in vivo. NrasG12V expression number of NrasG12V expressing senescent Taken together, our study shows that
in hepatocytes was accompanied by the cells was followed over time. We found a continuous, CD4 T-cell mediated
inductionofacellularsenescenceresponse. thattheimmuneclearanceofpre-cancerous immune clearance of pre-malignant
Senescent NrasG12V expressing hepatocytes NrasG12V expressing hepatocytes was abro- senescent cells is crucial to suppress
were found to express a myriad of cyto- gated in severe combined immunodefi- liver cancer development. Conversely, an
kines and chemokines, which led to the cient (SCID) mice and also in CD4 impaired immune clearance of premalig-
attraction of innate as well as adaptive knockout mice. Strikingly, the missing nant senescent hepatocytes was shown to
immune cells. These different immune immune clearance of NrasG12V expressing result in the development of liver carcino-
cell populations were found in close pre-cancerous cells in these mice resulted mas. Our study suggests that a small
proximity to senescent, NrasG12V expres- inthedevelopmentofhepatocellularcarci- subfraction of senescent hepatocytes can
sing hepatocytes. In accordance with the nomas atlater time points. Enzyme-linked escape their cell cycle arrest if there is
hypothesis that attracted immune cells immunospot (ELISPOT) assays revealed no immune clearance of these cells.
could mediate the clearance of senescent the presence of mutant Nras-specific However, a direct demonstration of this
*Correspondenceto:LarsZender;Email:[email protected]
Submitted:12/20/11;Accepted:12/20/11
http://dx.doi.org/10.4161/onci.19128
www.landesbioscience.com OncoImmunology 397
(SV40) large T antigen did not result in
efficient immune responses against these
hepatocytes5 but rather resulted in the
growth of liver carcinomas and tumor-
specific T cells were found to produce
TGFβ rather than IFNc. Our data may
help to resolve some of the controversy,
as it suggests that the induction of a
specific immune response against pre-
cancerous cells is dependent on an
intact cellular senescence response.
Therefore, immune surveillance against
pre-cancerous cells may occur if the
senescence program is engaged after the
occurrence of an oncogenic event.
However, if the induction of the cellular
senescence program is affected, e.g., due
to impaired p53 function or reduced
levels of p14Arf (p19Arf in mice), a specific
immune response against such tumor
prone cells may not occur. The fact that
Figure1.Clearanceofpre-malignantsenescentcellsthroughaCD4T-cellmediatedimmune
SV40 is known to disable senescence
response.Upontheaberrantactivationofoncogenescellscaneitherundergoapoptosisorcellular
senescence.Pre-malignantsenescenthepatocytesaresubjecttoacontinuousCD4T-cellmediated inductionmayexplainthelackofimmune
immuneclearancewhichiscrucialforlivercancersuppression.CD4T-cellsdependonmonocytes/ surveillance of SV40 expressing hepato-
macrophagestoexecutethekillingofpre-malignantsenescenthepatocytes. cytes in the study by Blankenstein and
colleagues.5
senescence escape remains subject for numbers of senescent hepatocytes were Future studies are needed to character-
future studies. found in both cohorts, thus supporting ize whether immune surveillance of pre-
Finally we also addressed whether there thatimmunesurveillanceofsenescentcells cancerous senescent cells also occurs in
is evidence for immune surveillance of also occurs in humans. other organs. Also, a deeper characteriza-
senescent hepatocytes in humans. For this There has been a long scientific debate tion of the underlying mechanisms of
purpose, we quantified the numbers of regarding the significance of a T-cell senescence surveillance, especially the
senescent hepatocytes in patients under dependent immune surveillance mech- individual contribution of involved cyto-
immunosuppressive therapy (due to anism of pre-cancerous cells (reviewed in and chemokines secreted from senescent
organ transplantation) or in patients ref. 4). For example, an elegant recent cells is needed. Such studies may pave
with HIV infection, both conditions that study showed that spontaneous intra- the way to eventually harness this process
impact CD4 T-cell function. Increased hepatic activation of the Simian virus 40 for cancer prevention and therapy.
References 3. Kang TW, Yevsa T, Woller N, Hoenicke L, 5. WillimskyG,BlankensteinT.Sporadicimmunogenic
WuestefeldT,DauchD,etal.Senescencesurveillance tumoursavoiddestructionbyinducingT-celltolerance.
1. Lowe SW, Cepero E, Evan G. Intrinsic tumour of pre-malignant hepatocytes limits liver cancer Nature2005;437:141-6;PMID:16136144;http://dx.
suppression. Nature 2004; 432:307-15; PMID: development. Nature 2011; 479:547-51; PMID: doi.org/10.1038/nature03954
15549092;http://dx.doi.org/10.1038/nature03098 22080947;http://dx.doi.org/10.1038/nature10599
2. Narita M, Lowe SW. Senescence comes of age. Nat 4. SwannJB,SmythMJ.Immunesurveillanceoftumors.
Med2005;11:920-2;PMID:16145569;http://dx.doi. J Clin Invest 2007; 117:1137-46; PMID:17476343;
org/10.1038/nm0905-920 http://dx.doi.org/10.1172/JCI31405
398 OncoImmunology Volume1Issue3
