Radiotherapy orchestrates natural killer cell dependent antitumor immune responses through CXCL8

Walle, Thomas; Kraske, Joscha A.; Liao, Boyu; Lenoir, Bénédicte; Timke, Carmen; Halbach, Emilia von Bohlen Und; Tran, Florian; Griebel, Paul; Albrecht, Dorothee; Ahmed, Azaz; Suarez-Carmona, Meggy; Jiménez-Sánchez, Alejandro; Beikert, Tizian; Tietz-Dahlfuß, Alexandra; Menevse, Ayse Nur; Schmidt, Gabriele; Brom, Manuela; Pahl, Jens; Antonopoulos, Wiebke; Miller, Matthias; Perez, Ramon Lopez; Bestvater, Felix; Giese, Nathalia A.; Beckhove, Philipp; Rosenstiel, Philip; Jäger, Dirk; Strobel, Oliver; Pe’er, Dana; Halama, Niels; Debus, Jürgen; Cerwenka, Adelheid; Huber, Peter E.

doi:10.1126/sciadv.abh4050

Cited by 83 publications

(45 citation statements)

References 70 publications

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“…Recent work has addressed this concern by locally augmenting chemokine concentrations using a mesothelin-targeting antibody fusion protein loaded with CXCL16, which is cleaved in the TME upon tumour cell engagement 186 . Furthermore, recent work has highlighted the application of radiation-induced CXCL8 to enhance NK cell migration to the tumour 188 . Last, chemokine–receptor interactions may be context-specific, either promoting or abrogating NK cell homing depending on the specific tumour type in question, as has been previously observed 184 , 185 .…”

Section: Enhancing Nk Cell Fitness and Antitumour Functionmentioning

confidence: 99%

Natural killer cells in antitumour adoptive cell immunotherapy

2022

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Natural killer (NK) cells comprise a unique population of innate lymphoid cells endowed with intrinsic abilities to identify and eliminate virally infected cells and tumour cells. Possessing multiple cytotoxicity mechanisms and the ability to modulate the immune response through cytokine production, NK cells play a pivotal role in anticancer immunity. This role was elucidated nearly two decades ago, when NK cells, used as immunotherapeutic agents, showed safety and efficacy in the treatment of patients with advanced-stage leukaemia. In recent years, following the paradigm-shifting successes of chimeric antigen receptor (CAR)-engineered adoptive T cell therapy and the advancement in technologies that can turn cells into powerful antitumour weapons, the interest in NK cells as a candidate for immunotherapy has grown exponentially. Strategies for the development of NK cell-based therapies focus on enhancing NK cell potency and persistence through co-stimulatory signalling, checkpoint inhibition and cytokine armouring, and aim to redirect NK cell specificity to the tumour through expression of CAR or the use of engager molecules. In the clinic, the first generation of NK cell therapies have delivered promising results, showing encouraging efficacy and remarkable safety, thus driving great enthusiasm for continued innovation. In this Review, we describe the various approaches to augment NK cell cytotoxicity and longevity, evaluate challenges and opportunities, and reflect on how lessons learned from the clinic will guide the design of next-generation NK cell products that will address the unique complexities of each cancer.

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Section: Enhancing Nk Cell Fitness and Antitumour Functionmentioning

confidence: 99%

Natural killer cells in antitumour adoptive cell immunotherapy

2022

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“…On the contrary, RT has been successfully employed to drive NK cell infiltration in experimental mammary tumors [ 66 , 67 ] and PDACs [ 68 ], via a mechanism that involved CXCL16 and CXCL8 secretion, respectively. However, CXCL8 has been associated with immunoevasion, tumor progression and resistance to (immuno)therapy in a variety of oncological settings [ 69 , 70 ].…”

Section: Environmental Obstacles For Optimal Nk Cell Anticancer Activitymentioning

confidence: 99%

“…Moreover, at least in some oncological indications, high intratumoral levels of CX3CL1 have been associated with dismal prognosis [65], calling for at least some caution on strategies that would increase the intratumoral levels of this cytokine. On the contrary, RT has been successfully employed to drive NK cell infiltration in experimental mammary tumors [66,67] and PDACs [68], via a mechanism that involved CXCL16 and CXCL8 secretion, respectively. However, CXCL8 has been associated with immunoevasion, tumor progression and resistance to (immuno) therapy in a variety of oncological settings [69,70].…”

Section: Table 1 (Continued)mentioning

confidence: 99%

NK cells and solid tumors: therapeutic potential and persisting obstacles

et al. 2022

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Natural killer (NK) cells, which are innate lymphocytes endowed with potent cytotoxic activity, have recently attracted attention as potential anticancer therapeutics. While NK cells mediate encouraging responses in patients with leukemia, the therapeutic effects of NK cell infusion in patients with solid tumors are limited. Preclinical and clinical data suggest that the efficacy of NK cell infusion against solid malignancies is hampered by several factors including inadequate tumor infiltration and persistence/activation in the tumor microenvironment (TME). A number of metabolic features of the TME including hypoxia as well as elevated levels of adenosine, reactive oxygen species, and prostaglandins negatively affect NK cell activity. Moreover, cancer-associated fibroblasts, tumor-associated macrophages, myeloid-derived suppressor cells, and regulatory T cells actively suppress NK cell-dependent anticancer immunity. Here, we review the metabolic and cellular barriers that inhibit NK cells in solid neoplasms as we discuss potential strategies to circumvent such obstacles towards superior therapeutic activity.

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“…Accumulating evidence indicates that radiotherapy treatment induces not only systemic anti-tumor immunity [43,44] by increasing NK and CD8 + CTL in ltration and reducing the level of invasive regulatory T cells (Treg) [45], but also tumor recurrence and metastasis, by "awakening" cancer stem cells or improving myeloid cells recruitment [46][47][48]. Tumor self-seeding and the formation of distal premetastatic niche are the characters for triple negative breast cancers (TNBC) metastasis [14,49,50].…”

Section: Discussionmentioning

confidence: 99%

Local Radiotherapy for Murine Breast Cancer Increases Risk of Metastasis by Promoting the Recruitment of M-MDSCs in Lung

Zhang

Yao

Cui

et al. 2022

Preprint

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Background Explore how exosomes released by X-ray irradiated tumor cells promote the formation of pulmonary metastatic nodules by inducing the recruitment of MDSCs to the lung. Methods BALB/c mice were injected with 4T1 tumor cells into the mammary adipose pad and allowed to grow for 28 days. On the 10th day of tumor inoculating, the primary tumor was irradiated by X-ray with a single dose of 20Gy. The mice were monitored for tumor growth, the number of pulmonary metastasis nodules and frequency of MDSCs. Antibody microarray and ELISA methods were used to analyze the altered cytokines (G-CSF, GM-CSF and CXCL1) in exosomes released by 4T1 cells after X-ray irradiation. The effects of the exosomes on the recruitment of MDSCs in the lung and facilitating the colonization of 4T1 in the lung were observed in normal BALB/c mice. Transwell method was used to observe the promotion of MDSCs migration by exosomes, lung tissue extracts from 4T1 tumor-bearing mice and GM-CSF via CCR2/CXCR2 signals, meanwhile, the effect of MDSCs on T lymphocytes function and migration of 4T1 cells were observed by the co-culture system. Results Even though radiotherapy reduced the burden of primary tumors and larger lung metastatic nodules (≥ 0.5 mm2), the number of smaller metastases (< 0.5 mm2) significantly increased. In addition, radiotherapy markedly potentiated M-MDSCs and reduced PMN-MDSCs recruitment in lung of 4T1 tumor-bearing mice. Moreover, the frequency of M-MDSCs in lung was positively correlated with the number of smaller metastatic nodules. Using co-culture experiments, we provided evidence that M-MDSCs of the lung in 4T1 tumor-bearing mice markedly inhibited T cell proliferation and killing activity, while M-MDSCs and PMN-MDSCs had a similar role in facilitating tumor cell dissemination. The G-CSF, GM-CSF and CXCL1 rich exosomes derived from irradiated 4T1 (ir/4T1-exo) could facilitate both M-MDSCs and PMN-MDSCs migration by CXCL1/CXCR2 signal. While the lung tissue extracts of irradiated mice or culture medium of macrophage treated with ir/4T1-exo showed an obvious tendency to chemotaxis on M-MDSCs. Mechanistically, ir/4T1-exo could induce macrophage to produce GM-CSF, which in turn further promoted CCL2 release in an autocrine manner to recruit M-MDSCs via CCL2/CCR2 axis. Conclusions Our work has identified an undesired effect of radiotherapy promoting immunosuppressive premetastatic niches by recruiting M-MDSCs to lung. Further studies on RT combined inhibition of CXCR2 or CCR2 signals were necessary.

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Radiotherapy orchestrates natural killer cell dependent antitumor immune responses through CXCL8

Cited by 83 publications

References 70 publications

Natural killer cells in antitumour adoptive cell immunotherapy

Natural killer cells in antitumour adoptive cell immunotherapy

NK cells and solid tumors: therapeutic potential and persisting obstacles

Local Radiotherapy for Murine Breast Cancer Increases Risk of Metastasis by Promoting the Recruitment of M-MDSCs in Lung

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