INSIGHTS | PERSPECTIVES
sciencemag.org SCIENCEGRAPHIC: A. KITTERMAN/SCIENCEcancer ( 3 ). The CDK4/6 inhibitors abemaci-
clib, ribociclib, and palbociclib have been
approved for use in breast cancer ( 4 ). Ru-
scetti et al. screened several chemotherapy
agents and identified MEK and CDK4/6 in-
hibitors as potent inducers of the senescent
phenotype in the KP (Kras and p53) mouse
model of lung adenocarcinoma.
Cellular senescence is a programmed
change in cell state associated with per-
manent growth inhibition ( 5 ). It can be
induced by stresses, such as DNA dam-
age, shortening of telomeres (a biomarker
of aging), oncogenic mutations, metabolic
mitochondrial dysfunction, and inflamma-
tion. The senescence-associated secretory
phenotype (SASP) is characterized by in-
creased production of growth factors, pro-
teases, and proinflammatory cytokines that
recruit immune cells and stimulate them to
clear the senescent cells. The precise mech-
anisms by which senescence is induced
and the affected cells eliminated remain
to be elucidated. Ruscetti et al. show that
the treatment of tumor cells with MEK and
CDK4/6 inhibitors selectively triggers the
antitumor functions of NK cells.
NK cells are innate lymphoid cells (ILCs)
with potent antitumor activities ( 6 ). The effi-
cacy of some conventional anticancer agents,
such as those used in chemotherapy, is not
exclusively due to the direct killing of the
tumor cells. Instead, some anticancer treat-
ments can induce forms of cancer cell stress
or death that alert the immune system, initi-
ating an antitumor immune response ( 7 ). NK
cells can be involved in these mechanisms.
For instance, telomeric repeat–binding factor
2 (TRF-2) has been shown to induce a form of
cellular stress that promotes the elimination
of neoplastic cells in an NK cell–dependent
manner ( 8 ). In addition, expression of ligands
for NK cell–activating receptors, NKG2D and
DNAM1, can be increased in cancer cells un-
dergoing stress-induced senescent programs
following treatment with chemotherapeu-
tic agents, leading to NK cell activation ( 9 ).
Senescent noncancer cells, such as decidual
cells ( 10 ), fibroblasts ( 11 ), and hepatic stellate
cells ( 12 ), can also trigger NK cell responses.
Given the dual potential of cellular se-
nescence to halt the proliferation of tumor
cells and recruit immune cells, interest in
pro-senescence therapies for cancer treat-
ment has been growing. However, several
hurdles remain on the road to therapy-
induced senescence as a means of treating
cancer: optimization of the dose sched-ules and combinations required to induce
cellular senescence and antitumor immu-
nity, while overcoming the protumorigenic
properties of senescent cells and the SASP.
Indeed, the SASP has been described as a
double-edged sword, because it can also
induce tumor-promoting effects such as an-
giogenesis, epithelial-to-mesenchymal tran-
sition, and metastasis ( 13 ). It thus remains
unclear whether it is preferable to induce
senescence rather than cell death.
To date, attempts to make use of NK cells
in cancer immunotherapy have focused on
the initiation of a multilayered immune
response culminating in protective and
long-lasting antitumor immunity ( 6 ). Re-
markably, Ruscetti et al. suggest that NK
cells act as a natural senolytic, eliminating
tumor cells rendered senescent by chemo-
therapy and controlling cancers withoutthe assistance of other immune cell types.
These findings raise important questions
about the mechanisms by which senescent
tumor cells are eliminated by NK cells and
whether NK cells kill senescent tumor cells
directly. Is the production of cytokines by
NK cells, such as interferon-g and GM-CSF
(granulocyte-macrophage colony-stimulat-
ing factor), involved? Moreover, NK cells
have many features in common with ILC1s
( 14 ). The selective involvement of NK cells
in the control of KP tumors is striking, but
its demonstration was based on the use of
an NK1.1 monoclonal antibody that depletes
both NK cells and ILC1s in mice. NK cells,
ILC1s, and an intermediate subset (intILC1)
can infiltrate mouse tumors and have op-
posing functions: NK cells favor tumor
control, whereas intILC1s and ILC1s do
not ( 15 ). Further dissection of the role of
MEK and CDK4/6 inhibitors, and of other
chemotherapy agents, in the composition
and function of tumor-infiltrating ILCs is
required. Does the recognition of senescent
cells by NK cells initiate long-term protec-
tion against nonsenescent tumor cells? And
most importantly, do these observations ap-
ply to human cancers?
Recent clinical results have supported the
hypothesis that chemotherapy can boost
immune responses and sensitize tumors to
immunotherapies. However, we still know
little about the underlying mechanisms, and
more explorations are required to identify
the most promising chemotherapy-immu-
notherapy combinations to further enhance
clinical responses in cancer patients. The
induction of senescence is one possible way
in which chemotherapy and immunity may
be able to join forces. j
REFERENCES AND NOTES- Cancerprogressreport.org, American Association for
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Oncol. 14 , 463 (2017). - J. R.-E. Choo, S.-C. Lee, Expert Opin. Drug Metab. Toxicol.
14 , 1123 (2018). - S. He, N. E. Sharpless, Cell 169 , 1000 (2017).
- L. Chiossone, P.-Y. Dumas, M. Vienne, E. Vivier, Nat. Rev.
Immunol. 18 , 671 (2018). - L. Galluzzi et al., Cancer Cell 28 , 690 (2015).
- A. Biroccio et al., Nat. Cell Biol. 15 , 818 (2013).
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- P. J. Brighton et al., eLife 11 , 6 (2017).
- A. Sagiv et al., Aging (Albany N.Y.) 8 , 328 (2016).
- H. Jin et al., Cell. Signal. 33 , 79 (2017).
- T. Saleh et al., Front. Oncol. 8 , 164 (2018).
- E. Vivier et al., Cell 174 , 1054 (2018).
- Y. Gao et al., Nat. Immunol. 18 , 1004 (2017).
ACKNOWLEDGMENTS
E.V. receives funding from the European Research Council
(TILC, no. 694502), the Agence Nationale de la Recherche,
Equipe Labelisée “La Ligue,” MSDAvenir, Innate Pharma,
and institutional grants to CIML (INSERM, CNRS, and Aix-
Marseille University) and to Marseille Immunopole. E.V. and
S.C. are Innate Pharma employees.
10.1126/science.aav7871
MEK and
CDK4/6
inhibitorsCancer cell Senescent cancer cell NK cell Activated NK cellSASPDoes the recognition
of senescent cells by
NK cells initiate
long-term protection
against nonsenescent
tumor cells?What is the composition
(NK cells, ILC1s, ...?) and
function of tumor-
infltrating ILCs?By what mechanisms are senescent tumor
RAS cells eliminated by NK cells?
RAF
MEK1/2
ERK1/2
CDK4/6 RB1356 21 DECEMBER 2018 • VOL 362 ISSUE 6421
NK cells detect and eliminate senescent tumor cells
Pharmacological inhibition of MEK and CDK4/6 induces retinoblastoma (RB) protein–mediated cellular
senescence and SASP, leading to the activation of NK cells, which detect and eliminate senescent tumor cells.
Several questions remain to be addressed, as indicated.
Published by AAASon December 20, 2018^http://science.sciencemag.org/Downloaded from