Cancer Cell

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Stressing Out about Cancer Immunotherapy

Xue-Yan He,1 David Ng,1 Linda Van Aelst,1 and Mikala Egeblad1,*
1Cold Spring Harbor Laboratory, Cancer Center, Cold Spring Harbor, NY 11724, USA

*Correspondence: egeblad@cshl.edu
https://doi.org/10.1016/j.ccell.2019.10.013

Stress has long been suspected to negatively influence cancer mortality, yet the molecular mechanisms
responsible for this effect have only recently been identified. A new study identifies a stress-induced
response in dendritic cells—the activation of the glucocorticoid-inducible transcriptional regulator
TSC22D3—as a potent, immunosuppressive effect of stress on cancer.

Intrinsic (genetic and epigenetic) changes the use of synthetic glucocorticoids in can-
in cancer cells and extrinsic changes cer treatment. Here, we discuss another
occurring to the microenvironment and newly identified mechanism by which
organism together drive cancer progres- glucocorticoid receptor signaling pro-
sion and resistance to therapy. One motes cancer and resistance to therapy,
extrinsic factor long suspected to drive namely by affecting dendritic cells’ (DCs)
cancer progression is stress. Stress is a ability to suppress the immune response
complex physiological process initiated against tumors (Yang et al., 2019).
by environmental or psychosocial factors, Yang and coworkers took advantage of
including social isolation, that leads to a two mouse models that have been used
cascade of systemic effects, starting extensively in studies of stress-related
with the processing of information in the disorders—the social defeat and the
central nervous system (Moreno-Smith acute restraint models. They combined
et al., 2010). The stress response involves these stress models with models of non-
secretion of corticotropin-releasing hor- small-cell lung cancer (NSCLC) (caused
mone from the hypothalamus, which by the carcinogen urethane) and colon
leads to the release of adrenocorticotro- cancer (caused by the carcinogen azoxy-
phic hormone from the anterior pituitary, methane and the inflammatory agent
in turn resulting in secretion of glucocorti- dextran sodium sulfate) and found that
coids from the adrenal gland (McEwen, social defeat causes an increase in the
2007). Cancer patients experience many number and size of tumors. In addition,
different types of stress, including the social defeat stress dampened the thera-
acute stress of getting the cancer diag- peutic response to oxaliplatin, a type of
nosis and the chronic stress of worrying chemotherapy that acts in part by
about recurrence or undergoing weeks inducing immunogenic cell death to
of chemo- or radiotherapy. Epidemiolog- mount an immune response against the
ical and clinical studies have provided ev- tumor. Additionally, social defeat and sus-
idence for links between stress or social tained acute restraint stress also reduced
isolation and cancer development and responses to immunogenic chemo-
survival (Moreno-Smith et al., 2010; Seph- therapy, prophylactic tumor vaccination,
ton et al., 2000). Yet, very little is known and PD-1-targeted immunotherapy in
about the mechanisms by which stress two transplanted fibrosarcoma and
promotes cancer. NSCLC models.
Recent studies have indicated that Next, Yang and coworkers identified
stress hormones, particularly glucocorti- corticosterone, a glucocorticoid and major
coids, have a dark side that can negatively stress hormone in mice, as the main
influence cancer treatment response neuroendocrine stress mediator linking
(Arbour et al., 2018; Obradovic
et al., stress and immunosuppression. A gluco-
2019). Notably, Obradovic
and coworkers corticoid receptor antagonist, mifepris-
reported earlier this year that activation of tone, efficiently abolished the immunosup-
glucocorticoid receptor signaling in cancer pressive effect of stress on chemotherapy,
cells, via ROR1 kinase signaling, results in and conversely, synthetic glucocorticoids
increased metastatic colonization and attenuated the therapeutic effects of tumor
resistance to chemotherapy (Obradovic
vaccination and chemotherapy in un-
et al., 2019), thus raising concerns about stressed mice. These data show that
stress-induced elevation in glucocorticoid
levels triggers an immunosuppressive
state that dampens chemo- and immuno-
therapeutic effects.
Cancer immunotherapy harnesses and
enhances the immune system to fight can-
cer. Certain types of chemotherapy also
activate the immune system by inducing
so-called immunogenic cell death
(Figure 1A). This happens when chemo-
therapy-induced cancer cell death causes
the release of danger-associated molecu-
lar patterns (DAMPs), including calreticu-
lin, ATP, and HMGB1 from the malignant
cells (Kroemer et al., 2013). This, in turn, at-
tracts DCs and facilitates the uptake of tu-
mor antigens by such DCs, allowing them
to engage and stimulate tumor-antigen-
specific, cytotoxic T lymphocytes (CTLs)
through a process known as cross-pre-
sentation. These CTLs produce interferon
(IFN)-g and mediate long-term effects of
immunogenic chemotherapy. Yang and
coworkers showed that stress causes a
reduction of calreticulin expression in
DCs and exclusion of IFN-g expressing
CTLs in the tumors after chemotherapy,
likely causing the reduced anticancer
response in stressed mice (Yang et al.,
2019). Moreover, reduced plasma levels
of cytokines including IFN-b, interleukin
(IL)-15, IL-23A, and C-X-C motif ligand 9
(CXCL9) and CXCL10 indicated that stress
causes systemic immunosuppression.
Specialized, cross-presenting DCs
have emerged as a central cell type in
the stimulation of anti-cancer immune re-
sponses. However, analyzing RNA
expression profiles in tumor-infiltrating
DCs after chemotherapy, Yang and co-
workers found no evidence that stress
causes changes in lineage commitment
or differentiation of DCs. Instead,
they found increased expression of the
glucocorticoid-inducible transcriptional

468 Cancer Cell 36, November 11, 2019 ª 2019 Elsevier Inc.
Cancer Cell

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A
Immunogenic
Chemotherapy

Stress Induced
Glucocorticoids

B Stress Induced
Glucocorticoids
Immunogenic
Chemotherapy
Tsc22d3

Type I IFN responses:

IFN-E
CXCL1/9/10
...

Tumor Glucocorticoid
Dendritic Cell Tumor Cell TCR Glucocorticoid
Antigen Receptor D

Cytotoxic T Dying Glucocorticoid

MHC I IFN-J HSP90
Lymphocyte Tumor Cell Response Elements

Figure 1. A Stress-Glucocorticoid-Dendritic Cell Axis Compromises Therapy-Induced Antitumor Immunity

(A) Immunogenic chemotherapy causes the release of tumor antigens and danger-associated molecular patterns. The antigens are taken up by dendritic cells
(DCs), which cross-represent them to cytotoxic T lymphocytes (CTLs), activating the CTLs so they can kill the tumor cells.
(B) Yang and coworkers elegantly show that stress-induced glucocorticoids inhibit therapy-induced anti-tumor immunity, including after immunogenic
chemotherapy, by upregulating the glucocorticoid-inducible transcriptional regulator Tsc22 domain family protein 3 (Tsc22d3) in DCs. The mechanisms involved
likely include reduced expression of IFN-b, CXCL1/9/10, and CTL suppression (Yang et al., 2019). CXCL, C-X-C motif ligand; HSP90, heat shock protein 90; IFN,
interferon; MHC I, major histocompatibility complex I; TCR, T cell receptor.

regulator Tsc22 domain family protein 3
(Tsc22d3; also known as glucocorticoid-
induced leucine zipper, Gilz) in DCs from
mice exposed to stress (Figure 1B).
Transgenic overexpression of Tsc22d3 in
the DCs was sufficient to abolish the re-
sponses to immunogenic chemotherapy
and tumor vaccine in unstressed mice,
whereas stress-exposed mice lacking
Tsc22d3 specifically in DCs showed an
enhanced response to anti-PD-1 treat-
ment and immunogenic chemotherapy.
How Tsc22d3 caused immune suppres-
sion remains to be determined, but the
authors noted that the expression of
Calr, Ifnb1, Cxcl9, and Cxcl10 in the tu-
mor-infiltrating dendritic cells was
restored in mice lacking Tsc22d3 in DCs.
Modeling stress responses in animals
has obvious limitations due to the higher
awareness and emotional aptitude of hu-
mans, so do these findings from mice
translate to humans? Yang and co-
workers found that glucocorticoid levels
were higher in sera from patients with
colorectal cancer or NSCLC than in
healthy volunteers and that elevated
glucocorticoid levels correlated with a
high score for a negative mood (so-called
‘‘profile of mood states’’ score). Also,
TSC22D3 expression was higher in pe-
ripheral blood mononuclear cells from
cancer patients than from healthy volun-
teers and correlated with elevated cortisol
levels. Taken together, Yang et al. have
identified a new stress-glucocorticoid-
DC axis that compromises therapy-
induced antitumor immunity (Yang
et al., 2019).

Cancer Cell 36, November 11, 2019 469


Prior work showed that glucocorticoid
elevation induced by metabolic stress
suppresses intratumoral adaptive immu-
nity, causing failure of cancer immuno-
therapy (Flint et al., 2016). Thus, both psy-
chological and metabolic stress, via
glucocorticoids, have major effects on
cancer progression and treatment in
mice. Correspondingly, abnormal gluco-
corticoid levels, consistent with stress,
were reported to correlate with reduced
survival in breast cancer (Sephton et al.,
2000). Intriguingly, stress also modulates
the gastrointestinal microbiome (Rhee
et al., 2009), which can affect the efficacy
of cancer immune checkpoint therapy
(Gopalakrishnan et al., 2018). Collectively,
these studies suggest that psychological
support for cancer patients should be a
critical component of cancer treatment.
But the implications reach further: syn-
thetic glucocorticoids are widely used in
cancer treatment to combat side effects
of chemotherapy and to treat symptoms
related to advanced cancer. Multiple
groups have now highlighted that in ani-
mal models, glucocorticoids have clear
negative effects on the outcome of ther-
apy (Flint et al., 2016; Obradovic
et al.,
2019; Yang et al., 2019). In line with this,
glucocorticoid use was recently reported
to be associated with poorer outcome in
NSCLC patients treated with anti-PD-L1
(Arbour et al., 2018). Thus, the possibility
that synthetic glucocorticoid treatment
470 Cancer Cell 36, November 11, 2019
could be detrimental to treatment war-
rants further investigation.
Future work will hopefully clarify the
types and extent of stress that affect can-
cer progression and therapy responses in
people and will likely also identify addi-
tional mechanisms responsible for the ef-
fects of stress. Such knowledge may
enable devising strategies to reduce the
harmful effects of stress and allow syn-
thetic glucocorticoids to be used to con-
trol side effects and symptoms while pre-
venting them from promoting cancer
growth, metastasis, and therapy resis-
tance. The above-mentioned research
also highlights that cancer is not only a
disease of genomic, cell-biological, or
microenvironmental alterations but, in
addition, cancer relies on altered body
physiology. The interface between cancer
biology and physiology must therefore be
understood to ultimately achieve better
survival of cancer patients.
ACKNOWLEDGMENTS
M.E. and L.V.A. were supported by a grant from the
Simons Foundation to Cold Spring Harbor Labora-
tory. X.-Y.H. was supported by a fellowship from
the State of New York (contract #C150158).
REFERENCES
Arbour, K.C., Mezquita, L., Long, N., Rizvi, H.,
Auclin, E., Ni, A., Martı́nez-Bernal, G., Ferrara, R.,
Lai, W.V., Hendriks, L.E.L., et al. (2018). Impact of
baseline steroids on efficacy of Programmed Cell
Cancer Cell
Previews
Death-1 and Programmed Death-Ligand 1
blockade in patients with non-small-cell lung can-
cer. J. Clin. Oncol. 36, 2872–2878.
Flint, T.R., Janowitz, T., Connell, C.M., Roberts,
E.W., Denton, A.E., Coll, A.P., Jodrell, D.I., and
Fearon, D.T. (2016). Tumor-induced IL-6 repro-
grams host metabolism to suppress anti-tumor im-
munity. Cell Metab. 24, 672–684.
Gopalakrishnan, V., Helmink, B.A., Spencer, C.N.,
Reuben, A., and Wargo, J.A. (2018). The influence
of the gut microbiome on cancer, immunity, and
cancer immunotherapy. Cancer Cell 33, 570–580.
Kroemer, G., Galluzzi, L., Kepp, O., and Zitvogel, L.
(2013). Immunogenic cell death in cancer therapy.
Annu. Rev. Immunol. 31, 51–72.
McEwen, B.S. (2007). Physiology and neurobi-
ology of stress and adaptation: central role of the
brain. Physiol. Rev. 87, 873–904.
Moreno-Smith, M., Lutgendorf, S.K., and Sood,
A.K. (2010). Impact of stress on cancer metastasis.
Future Oncol. 6, 1863–1881.
Obradovic
, M.M.S., Hamelin, B., Manevski, N.,
Couto, J.P., Sethi, A., Coissieux, M.-M., Mu€nst,
S., Okamoto, R., Kohler, H., Schmidt, A., and
Bentires-Alj, M. (2019). Glucocorticoids promote
breast cancer metastasis. Nature 567, 540–544.
Rhee, S.H., Pothoulakis, C., and Mayer, E.A.
(2009). Principles and clinical implications of the
brain-gut-enteric microbiota axis. Nat. Rev.
Gastroenterol. Hepatol. 6, 306–314.
Sephton, S.E., Sapolsky, R.M., Kraemer, H.C., and
Spiegel, D. (2000). Diurnal cortisol rhythm as a pre-
dictor of breast cancer survival. J. Natl. Cancer
Inst. 92, 994–1000.
Yang, H., Xia, L., Chen, J., Zhang, S., Martin, V., Li,
Q., Lin, S., Chen, J., Calmette, J., Lu, M., et al.
(2019). Stress-glucocorticoid-TSC22D3 axis com-
promises therapy-induced antitumor immunity.
Nat. Med. 25, 1428–1441.