RESEARCH H I GHL I GHTS VOLUME 22 | MAY 2022 | 9 NATURE REVIEWS | CANCER www.nature.com/nrc 0123456789( ) ; : RE S EARCH H I GHL I GHT S 258 | MAY 2022 | VOLUME 22 Accumulating evidence suggests that host cells can induce local and systemic responses following cancer therapy to stimulate tumour progression. This led Nolan et al. to hypothesize that injury to healthy tissues resulting from off-target radiation may predispose to subsequent 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 metastatic 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 introduction of cancer cells showed that while there was DNA damage and senescence, there were no histological differences compared to control lung tissue. Yet, there was a specific enrichment of neutrophils present in a pro-inflammatory, activated state. Furthermore, irradiated mice lacking neutrophils had decreased 4T1 metastatic load in the lung indicating that radiation-primed neutrophils can alter the lung microenvironment to foster the growth of arriving cancer cells. Deeper analyses to ascertain how locally activated neutrophils 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 metastatic niche of irradiated lungs but also in the 4T1 cells themselves. Cancer cell stemness is known to be regulated by Notch signalling, and interestingly, the authors were able to show that 4T1 cells isolated from Notch high irradiated lungs had a greater capacity to form colonies in vitro compared with 4T1 cells from the Notch low 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) Credit: David Johnston/ Springer Nature Limited ME TAS TAS I S Naughty neutrophils It is remarkable how a malignant cell orchestrates the acquired modifications for the purpose of sustainable tumour growth. Hypoxia, drug resistance and a low number of immunogenic antigens seen in many cancers, including breast cancer, are common barriers to chemotherapeutic efficacy in the tumour microenvironment (TME), leading to treatment failures. As a result, in recent years, research into TME-modifying drugs that improve drug effectiveness and promote antitumour immunity has shown promise in extending overall patient survival. Amini et al. investigated a multimodal paradigm that combines bioreactive, TME-modulating hybrid polymer-lipid encapsulated manganese dioxide nanoparticles (PLMD-NPs) with doxorubicin (DOX). This combatted drug resistance mechanisms, reduced hypoxia and reversed immunosuppressive conditions 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 4hours 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 therapy 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) This research using TMEmodulating PLMD-NPs technology has, in my opinion, the potential to change the traditional approach to drug delivery BREAS T CANCER NANOTHERAPY: TARGETING THE TUMOUR MICROENVIRONMENT Journal Club
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