RESEARCH ARTICLE SUMMARY
◥IMMUNOLOGY
p21 produces a bioactive secretome that places
stressed cells under immunosurveillance
Ines Sturmlechner, Cheng Zhang, Chance C. Sine, Erik-Jan van Deursen, Karthik B. Jeganathan,
Naomi Hamada, Jan Grasic, David Friedman, Jeremy T. Stutchman, Ismail Can, Masakazu Hamada,
Do Young Lim, Jeong-Heon Lee, Tamas Ordog, Remi-Martin Laberge, Virginia Shapiro,
Darren J. Baker, Hu Li, Jan M. van Deursen
INTRODUCTION:Complex multicellular organ-
isms are subject to a myriad of cellular stresses,
which can be managed through cell-intrinsic
adaptation and repair mechanisms. Cells that
fail to recover activate programs that lead to
regulated cell death or cellular senescence,
thereby limiting the risk of neoplastic trans-
formation. Evidence is emerging that inter-
cellular communication also plays an important
role in dealing with cellular stresses. For in-
stance, cells experiencing DNA damage display
cell-surface ligands that facilitate lymphocyte
recognition and secrete cytokines that attract
myeloid cells. Furthermore, cells undergo-
ing cellular senescence generate a bioactive
secretome known as the senescence-associated
secretory phenotype (SASP), which facilitates
senescent cell (SNC) recognition by the im-
mune system.
RATIONALE:Stressed cells that become senes-
cent have been implicated in various biological
processes beyond cancer, including develop-
ment, tissue repair, aging, and age-related
diseases, presumably through the paracrine
actions of the SASP. To better understand
the molecular properties of SNCs, we sought
to identify key determinants of SNC identity
by screening for genes nearby senescence-
associated super-enhancers conserved across
stressors, cell types, and mammalian species.
Through this approach, we identifiedp21
(Cdkn1a), which encodes the cyclin-dependent
kinase (CDK) inhibitor p21, and conducted
an in-depth analysis of its functions from the
time cells first experience stress until they
have become senescent.RESULTS:We found that p21—in addition to its
function in maintaining the cell-cycle arrest
of SNCs—has a prominent role in establish-
ing the SASP through retinoblastoma protein
(Rb)–dependent transcription involving se-
lect SMAD and STAT transcription factors.Although this transcriptional program remains
active in SNCs, p21 initiates this program as a
first response to stress occurring in parallel with
cell-cycle arrest. The resulting immediate-early
secretome, which we term the p21-activated
secretory phenotype (PASP), comprises sev-
eral hundred factors, including the chemokine
CXCL14, which recruits macrophages to sur-
veil stressed cells with elevated p21. In mouse
liver, these macrophages disengage if cells
normalize p21 levels within 4 days after its
induction. However, if p21 remains elevated,
the adjoined macrophages polarize toward an
M1 phenotype, and cytotoxic T lymphocytes
arrive to execute target cell elimination when
classical markers of senescence are not yet
detectable. This scenario also occurs with
oncogenic KRAS-mediated p21 induction,
highlighting the physiological relevance of the
uncovered immunosurveillance mechanism to
tumor suppression. By contrast, CDK inhibitor
p16, which is often elevated in SNCs and also
halts cell-cycle progression through Rb hypo-
phosphorylation, does not induce immuno-
surveillance when overexpressed in mouse liver.
Although p16 induction yields an immediate-
early secretome that consists largely of factors
that overlap with the PASP, there are far fewer
factors, and CXCL14 is absent. Studies on CDK
inhibitor p27 further suggested that coordi-
nated induction of cell-cycle arrest and immu-
nosurveillance is a distinctive feature of p21.CONCLUSION:Our study demonstrates that
in response to cellular stress, p21 alters the
transcription regulatory properties of Rb to
not only inhibit genes required for cell-cycle
progression but also activate a large collec-
tion of genes implicated in diverse biological
functions, including immunosurveillance. By
promptly recruiting macrophages to stressed
cells, p21 sets a biological timer that allows for
a period in which stressed cells can recuperate,
thereby normalizing p21. This timer expires
when the immune response transitions from
a surveillance to a clearance mode. As such,
p21 provides a first line of defense against
dysfunctional cells that can become cancerous
or otherwise cause pathology. Given that p21
is a p53 target gene, it will be important to
define whether this p21-controlled immuno-
clearance mechanism is perturbed in cancer
cells that lack functional p53, and if so, to ex-
plore the therapeutic impact of interventions
that reactivate it.
▪RESEARCHSCIENCEscience.org 29 OCTOBER 2021•VOL 374 ISSUE 6567 577
The list of author affiliations is available in the full article online.
*Corresponding author. Email: [email protected]
(J.M.v.D.); [email protected] (H.L.)
Cite this article as I. Sturmlechneret al.,Science 374 ,
eabb3420 (2021). DOI: 10.1126/science.abb3420READ THE FULL ARTICLE AT
https://doi.org/10.1126/science.abb3420E2F S phase genesSMAD/STAT PASP genesStressors
(i.e.
KRASG12V)T cell
(cytotoxic)Stressed cell MΦ macrophageRbPASP (CXCL14)ImmunosurveillanceCell cycle arrestClearanceDisengaged
immune cellsday 0 day 2 day 6 day 8Rb(+ other)Rbday 4Arrest of and macrophage
recruitment by stressed cellsCycling
competent
cell HypophosphorylationB cellRepair timer
(PASP-based)p21 p21T cellSurveillancep21 induction no longer necessaryCyclinCDKp53 p2 1 p21 p2p21 (^1) p21p2 1
p21 places stressed cells under immunosurveillance.p21 induced by cells under duress activates an
Rb-dependent transcriptional program that produces CXCL14 and other secreted factors. CXCL14 promptly
recruits macrophages, which disengage if stressed cells recuperate and normalize p21 within 4 days.
However, if p21 induction persists, the adjoined macrophages polarize toward an M1 phenotype and cytotoxic
T cells arrive to eliminate target cells, including preneoplastic cells.