Research Highlights
M E TA S TA S I S
Naughty neutrophils
Accumulating evidence sug­
gests that host cells can
induce local and systemic
responses ­following
cancer therapy to stimu­
Springer Nature Limited
late tumour progression.
Credit: David Johnston/
This led Nolan et al. to
hypothesize that injury
to healthy tissues result­
ing from off-target
­radiation may pre­
dispose to s­ ubsequent
metastatic out­growth. To test their idea, the authors used a
mouse model of acute radiation exposure to the lung within
the setting of breast cancer metastasis to reveal that radiation
can create a pro-metastatic lung microenvironment, an effect
mediated by neutrophils.
To mimic off-target radiation exposure, mice were irradiated
with a single dose of focused radiation specifically to the
­thoracic cavity; after 4 days of recovery, these same mice were
then injected orthotopically with non-metastatic 4T07 or meta­
static 4T1 breast cancer cells to generate primary tumours.
Pre-exposure of healthy lung tissue in this way increased the
spontaneous metastatic propensity of both cell lines leading
to a large number of metastatic foci in the lungs of these mice
compared to a rare few present in the lungs of sham-irradiated,
control mice. This result was not exclusive to breast cancer cells
as lung irradiation prior to injection of human oesophageal and
NSCLC cell lines also stimulated metastatic colonization.
Examination of irradiated lung tissue before the intro­
duction of cancer cells showed that while there was DNA
damage and senescence, there were no histological differ­
ences compared to control lung tissue. Yet, there was a speci­
fic enrichment of neutrophils present in a pro-inflammatory,
activated state. Furthermore, irradiated mice lacking neutro­
phils had decreased 4T1 metastatic load in the lung indicat­
ing that radiation-primed neutrophils can alter the lung
­microenvironment to foster the growth of arriving cancer cells.
Deeper analyses to ascertain how locally activated neutro­
phils precondition lung tissue revealed that the presence of
neutrophils was sufficient to change the transcriptomic profile
of lung epithelial cells, which included an increase in genes
involved in Notch signalling. Importantly, Notch activation was
enriched not only in the epithelial compartment of the meta­
static niche of irradiated lungs but also in the 4T1 cells them­
selves. Cancer cell stemness is known to be regulated by Notch
signalling, and interestingly, the authors were able to show
that 4T1 cells isolated from Notchhigh irradiated lungs had
a greater capacity to form colonies in vitro compared with
4T1 cells from the Notchlow lungs of control mice.
This work calls for clinical studies exploring whether such
neutrophilic responses are similarly induced in patients with
cancer undergoing radiotherapy.
Anna Dart
Original article Nolan, E. et al. Radiation exposure elicits a neutrophil-driven
response in healthy lung tissue that enhances metastatic colonization. Nat. Cancer 3,
173–187 (2022)
Related article Shaked, Y. The pro-tumorigenic host response to cancer therapies.
Nat. Rev. Cancer 19, 667–685 (2019)
258 | MAY 2022 | volume 22 www.nature.com/nrc
Journal Club
BREAST CANCER
Nanotherapy: targeting the tumour
microenvironment
It is remarkable how a malignant cell orchestrates the
acquired modifications for the purpose of sustainable
tumour growth. Hypoxia, drug resistance and a low This research
number of immunogenic antigens seen in many cancers,
including breast cancer, are common barriers to chemo­
using TME-
therapeutic efficacy in the tumour micro­environment modulating
(TME), leading to treatment failures. As a result, in recent PLMD-NPs
years, research into TME-modifying drugs that improve technology has,
drug effectiveness and promote antitumour immunity
has shown promise in extending overall patient survival.
in my opinion,
Amini et al. investigated a multimodal paradigm the potential
that combines bioreactive, TME-modulating hybrid to change the
polymer-lipid encapsulated manganese dioxide
traditional
nanoparticles (PLMD-NPs) with doxorubicin (DOX).
This combatted drug resistance mechanisms, reduced approach to
hypoxia and reversed immunosuppressive conditions drug delivery
by stimulating innate and adaptive immune responses,
thereby blocking crosstalk between cancer cells and
tumour-associated macrophages (TAMs) and improving chemotherapy.
In mice bearing EMT6 breast tumour xenografts, combination treatment
with PLMD-NPs followed by DOX for 4 hours led to tumour shrinkage of
up to 60% compared with mice that were only treated with DOX (13%).
Tumour-infiltrating CD8+ T cells were elevated in the PLMD-NP and DOX ther­
apy group compared with the DOX-alone group. Further analysis showed that
PLMD-NPs altered the TME in favour of CD8+ T cell recruitment, proliferation
and activation, in addition to inducing cancer cell apoptosis and inhibiting
expression of drug resistance genes.
Further, an experiment involving a re-challenge of mice, whose tumours
had been excised following treatment, with EMT6 cells showed that seven out
of eight mice in the PLMD-NP and DOX group did not show tumour growth,
whereas rapid tumour growth was observed in the untreated control group
and moderate growth in the DOX-treated group. These PLMD-NP and DOX
treated and then rechallenged mice increased antitumour immunostimulatory
responses in contrast to the DOX-treated rechallenged mice.
In addition, the generation of nitric oxide by combination therapy caused
apoptotic cancer cell death, consistent with the observation of increased
M1 macrophage polarization and thus an inflammatory immune response.
In our own research, the cellular alterations of immune cells, and
DOX-induced cytotoxicity of PLMD-NPs in the TME reported by Amini et al.,
motivated us to search for compounds to be used in combination therapy via
nano delivery in solid tumours. Continuing our primary research on nano-drug
delivery to drug-resistant breast and prostate cancer, we plan to use this
approach to screen compounds in combination with nanotherapy that precisely
targets the cancer cells without compromising the immune cells. This research
using TME-modulating PLMD-NPs technology has, in our opinion, the potential
to change the traditional approach to drug delivery, resulting in improved
clinical translational results.
Santosh Kumar Singh and Rajesh Singh   
Department of Microbiology, Biochemistry & Immunology, Cancer Health Equity
Institute, Morehouse School of Medicine, Atlanta, GA, USA
✉e-mail: sksingh@msm.edu; rsingh@msm.edu
Competing interests
The authors declare no competing interests.
Original article Amini, M. A. et al. Combining tumor microenvironment modulating nanoparticles with
doxorubicin to enhance chemotherapeutic efficacy and boost antitumor immunity. J. Natl Cancer Inst. 111,
399–408 (2019)