Real-time ex vivo monitoring of NK cell migration toward obesity-associated oesophageal adenocarcinoma following modulation of CX3CR1.
Journal
Scientific reports
ISSN: 2045-2322
Titre abrégé: Sci Rep
Pays: England
ID NLM: 101563288
Informations de publication
Date de publication:
18 Feb 2024
18 Feb 2024
Historique:
received:
24
11
2023
accepted:
12
02
2024
medline:
19
2
2024
pubmed:
19
2
2024
entrez:
18
2
2024
Statut:
epublish
Résumé
Oesophagogastric adenocarcinomas (OAC) are poor prognosis, obesity-associated cancers which may benefit from natural killer (NK) cell-based immunotherapies. Cellular immunotherapies encounter two key challenges to their success in OAC, namely recruitment to extratumoural tissues such as the omentum at the expense of the tumour and an immunosuppressive tumour microenvironment (TME) which can hamper NK cell function. Herein, we examined approaches to overcome the detrimental impact of obesity on NK cells and NK cell-based immunotherapies. We have demonstrated that NK cells migrate preferentially to the chemotactic signals of OAC patient-derived omentum over tumour in an ex vivo model of immune cell migration. We have identified CX3CR1 modulation and/or tumour chemokine profile remodelling as approaches to skew NK cell migration towards tumour. We also report targetable immunosuppressive facets of the obese OAC TME which dampen NK cell function, in particular cytotoxic capabilities. These data provide insights into approaches to therapeutically overcome key challenges presented by obesity and will inform superior design of NK cell-based immunotherapies for OAC.
Identifiants
pubmed: 38369570
doi: 10.1038/s41598-024-54390-5
pii: 10.1038/s41598-024-54390-5
doi:
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
4017Subventions
Organisme : Breakthrough Cancer Research
ID : BCR-2019-02-PhD-TCD
Organisme : Breakthrough Cancer Research
ID : CIRF-2022-01
Organisme : Breakthrough Cancer Research
ID : CIRF-2022-01
Informations de copyright
© 2024. The Author(s).
Références
Lauby-Secretan, B. et al. Body fatness and cancer—Viewpoint of the IARC Working Group. N. Engl. J. Med. 375, 794–798 (2016).
pubmed: 27557308
pmcid: 6754861
doi: 10.1056/NEJMsr1606602
Hoyo, C. et al. Body mass index in relation to oesophageal and oesophagogastric junction adenocarcinomas: A pooled analysis from the international BEACON consortium. Int. J. Epidemiol. 41, 1706–1718 (2012).
pubmed: 23148106
pmcid: 3535758
doi: 10.1093/ije/dys176
Siegel, R. L., Miller, K. D. & Jemal, A. Cancer statistics, 2020. CA Cancer J. Clin. 70, 7–30 (2020).
pubmed: 31912902
doi: 10.3322/caac.21590
van Hagen, P. et al. Preoperative chemoradiotherapy for esophageal or junctional cancer. N. Engl. J. Med. 366, 2074–2084 (2012).
pubmed: 22646630
doi: 10.1056/NEJMoa1112088
ASCO. Stomach Cancer: Statistics. Cancer.net. www.cancer.net/cancer-types/stomach-cancer/statistics (2021).
Ajani, J. A. et al. Multi-institutional trial of preoperative chemoradiotherapy in patients with potentially resectable gastric carcinoma. J. Clin. Oncol. 22, 2774–2780 (2004).
pubmed: 15254045
doi: 10.1200/JCO.2004.01.015
Ajani, J. A. et al. Paclitaxel-based chemoradiotherapy in localized gastric carcinoma: Degree of pathologic response and not clinical parameters dictated patient outcome. J. Clin. Oncol. 23, 1237–1244 (2005).
pubmed: 15718321
doi: 10.1200/JCO.2005.01.305
Muro, K. et al. Pembrolizumab for patients with PD-L1-positive advanced gastric cancer (KEYNOTE-012): A multicentre, open-label, phase 1b trial. Lancet Oncol. 17, 717–726 (2016).
pubmed: 27157491
doi: 10.1016/S1470-2045(16)00175-3
Kojima, T. et al. Randomized phase III KEYNOTE-181 study of pembrolizumab versus chemotherapy in advanced esophageal cancer. J. Clin. Oncol. 38, 4138–4148 (2020).
pubmed: 33026938
doi: 10.1200/JCO.20.01888
Mylod, E., Lysaght, J. & Conroy, M. J. Natural killer cell therapy: A new frontier for obesity-associated cancer. Cancer Lett. 535, 215620 (2022).
pubmed: 35283210
doi: 10.1016/j.canlet.2022.215620
Ishigami, S. et al. Prognostic value of intratumoral natural killer cells in gastric carcinoma. Cancer 88, 577–583 (2000).
pubmed: 10649250
doi: 10.1002/(SICI)1097-0142(20000201)88:3<577::AID-CNCR13>3.0.CO;2-V
Imai, K., Matsuyama, S., Miyake, S., Suga, K. & Nakachi, K. Natural cytotoxic activity of peripheral-blood lymphocytes and cancer incidence: An 11-year follow-up study of a general population. Lancet 356, 1795–1799 (2000).
pubmed: 11117911
doi: 10.1016/S0140-6736(00)03231-1
Xu, B. et al. Prognostic value of tumor infiltrating NK cells and macrophages in stage II+III esophageal cancer patients. Oncotarget 7, 74904–74916 (2016).
pubmed: 27736796
pmcid: 5342711
doi: 10.18632/oncotarget.12484
Nersesian, S. et al. NK cell infiltration is associated with improved overall survival in solid cancers: A systematic review and meta-analysis. Transl. Oncol. 14, 100930 (2021).
pubmed: 33186888
doi: 10.1016/j.tranon.2020.100930
Zhang, S. et al. Prognostic significance of tumor-infiltrating natural killer cells in solid tumors: A systematic review and meta-analysis. Front. Immunol. 11, 1242 (2020).
pubmed: 32714321
pmcid: 7343909
doi: 10.3389/fimmu.2020.01242
Mylod, E. et al. Fractalkine elicits chemotactic, phenotypic, and functional effects on CX3CR1 + CD27 − NK cells in obesity-associated cancer. J. Immunol. 207, 1200–1210 (2021).
pubmed: 34321227
doi: 10.4049/jimmunol.2000987
O’Shea, D. & Hogan, A. E. Dysregulation of natural killer cells in obesity. Cancers (Basel) 11, 573 (2019).
pubmed: 31018563
doi: 10.3390/cancers11040573
Bähr, I., Spielmann, J., Quandt, D. & Kielstein, H. Obesity-associated alterations of natural killer cells and immunosurveillance of cancer. Front. Immunol. 11, 245 (2020).
pubmed: 32231659
pmcid: 7082404
doi: 10.3389/fimmu.2020.00245
Lynch, L. A. et al. Are natural killer cells protecting the metabolically healthy obese patient?. Obesity 17, 601–605 (2009).
pubmed: 19238145
doi: 10.1038/oby.2008.565
Kim, M., Kim, M., Yoo, H. J. & Lee, J. H. Natural killer cell activity and interleukin-12 in metabolically healthy versus metabolically unhealthy overweight individuals. Front. Immunol. 8, 1700 (2017).
pubmed: 29238351
pmcid: 5712537
doi: 10.3389/fimmu.2017.01700
Michelet, X. et al. Metabolic reprogramming of natural killer cells in obesity limits antitumor responses. Nat. Immunol. 19, 1330–1340 (2018).
pubmed: 30420624
doi: 10.1038/s41590-018-0251-7
Conroy, M. J. et al. CCR1 antagonism attenuates T cell trafficking to omentum and liver in obesity-associated cancer. Immunol. Cell Biol. 94, 531–537 (2016).
pubmed: 27046081
doi: 10.1038/icb.2016.26
Conroy, M. J. et al. The microenvironment of visceral adipose tissue and liver alter natural killer cell viability and function. J. Leukoc. Biol. 100, 1435–1442 (2016).
pubmed: 27365528
doi: 10.1189/jlb.5AB1115-493RR
Conroy, M. J. et al. Identifying a novel role for fractalkine (CX3CL1) in memory CD8+ T cell accumulation in the omentum of obesity-associated cancer patients. Front. Immunol. 9, 1867 (2018).
pubmed: 30150990
pmcid: 6099201
doi: 10.3389/fimmu.2018.01867
Lin, E. W., Karakasheva, T. A., Hicks, P. D., Bass, A. J. & Rustgi, A. K. The tumor microenvironment in esophageal cancer. Oncogene 35, 5337–5349 (2016).
pubmed: 26923327
pmcid: 5003768
doi: 10.1038/onc.2016.34
Melo, A. M. et al. Tissue distribution of γδ T cell subsets in oesophageal adenocarcinoma. Clin. Immunol. 229, 108797 (2021).
pubmed: 34273585
doi: 10.1016/j.clim.2021.108797
Melo, A. M. et al. Mucosal-associated invariant T cells display diminished effector capacity in oesophageal adenocarcinoma. Front. Immunol. 10, 1580 (2019).
pubmed: 31354725
pmcid: 6635552
doi: 10.3389/fimmu.2019.01580
Lysaght, J. et al. T lymphocyte activation in visceral adipose tissue of patients with oesophageal adenocarcinoma. Br. J. Surg. 98, 964–974 (2011).
pubmed: 21520028
doi: 10.1002/bjs.7498
Lysaght, J. et al. Pro-inflammatory and tumour proliferative properties of excess visceral adipose tissue. Cancer Lett. 312, 62–72 (2011).
pubmed: 21890265
doi: 10.1016/j.canlet.2011.07.034
Conroy, M. J. et al. Parallel profiles of inflammatory and effector memory T cells in visceral fat and liver of obesity-associated cancer patients. Inflammation 39, 1729–1736 (2016).
pubmed: 27423204
doi: 10.1007/s10753-016-0407-2
Schlecker, E. et al. Metalloprotease-mediated tumor cell shedding of B7–H6, the ligand of the natural killer cell-activating receptor NKp30. Cancer Res. 74, 3429–3440 (2014).
pubmed: 24780758
doi: 10.1158/0008-5472.CAN-13-3017
Mylod, E. et al. Investigating the susceptibility of treatment-resistant oesophageal tumours to natural killer cell-mediated responses. Clin. Exp. Med. https://doi.org/10.1007/s10238-022-00811-6 (2022).
doi: 10.1007/s10238-022-00811-6
pubmed: 35364779
pmcid: 10224847
Zingoni, A., Vulpis, E., Loconte, L. & Santoni, A. NKG2D ligand shedding in response to stress: Role of ADAM10. Front. Immunol. 11, 447 (2020).
pubmed: 32269567
pmcid: 7109295
doi: 10.3389/fimmu.2020.00447
Ponath, V. et al. Secreted ligands of the NK cell receptor NKp30: B7–H6 is in contrast to BAG6 only marginally released via extracellular vesicles. Int. J. Mol. Sci. 22, 2189 (2021).
pubmed: 33671836
pmcid: 7926927
doi: 10.3390/ijms22042189
Mylod, E. et al. The omentum in obesity-associated cancer: A hindrance to effective natural killer cell migration towards tumour which can be overcome by CX3CR1 antagonism. Cancers (Basel) 14, 64 (2021).
pubmed: 35008227
doi: 10.3390/cancers14010064
Laue, T. et al. Altered NK cell function in obese healthy humans. BMC Obes. 2, 1 (2015).
pubmed: 26217516
pmcid: 4511543
doi: 10.1186/s40608-014-0033-1
Caligiuri, M. A. Human natural killer cells. Blood 112, 461–469 (2008).
pubmed: 18650461
pmcid: 2481557
doi: 10.1182/blood-2007-09-077438
Keating, S. E. et al. Metabolic reprogramming supports IFN-γ production by CD56 bright NK cells. J. Immunol. 196, 2552–2560 (2016).
pubmed: 26873994
doi: 10.4049/jimmunol.1501783
Donnelly, R. P. et al. mTORC1-dependent metabolic reprogramming is a prerequisite for NK cell effector function. J. Immunol. 193, 4477–4484 (2014).
pubmed: 25261477
doi: 10.4049/jimmunol.1401558
Choi, C. & Finlay, D. K. Optimising NK cell metabolism to increase the efficacy of cancer immunotherapy. Stem Cell Res. Ther. 12, 320 (2021).
pubmed: 34090499
pmcid: 8180160
doi: 10.1186/s13287-021-02377-8
Terrén, I., Orrantia, A., Vitallé, J., Zenarruzabeitia, O. & Borrego, F. NK cell metabolism and tumor microenvironment. Front. Immunol. 10, 2278 (2019).
pubmed: 31616440
pmcid: 6769035
doi: 10.3389/fimmu.2019.02278
Castriconi, R. et al. Transforming growth factor β1 inhibits expression of NKP30 and NKG2D receptors: Consequences for the NK-mediated killing of dendritic cells. Proc. Natl. Acad. Sci. U.S.A. 100, 4120–4125 (2003).
pubmed: 12646700
pmcid: 153058
doi: 10.1073/pnas.0730640100
Crane, C. A. et al. TGF-downregulates the activating receptor NKG2D on NK cells and CD8+ T cells in glioma patients. Neuro Oncol. 12, 7–13 (2010).
pubmed: 20150362
doi: 10.1093/neuonc/nop009
Gao, Y. et al. Tumor immunoevasion by the conversion of effector NK cells into type 1 innate lymphoid cells. Nat. Immunol. 18, 1004–1015 (2017).
pubmed: 28759001
doi: 10.1038/ni.3800
Trotta, R. et al. TGF-β utilizes SMAD3 to inhibit CD16-mediated IFN-γ production and antibody-dependent cellular cytotoxicity in human NK cells. J. Immunol. 181, 3784–3792 (2008).
pubmed: 18768831
doi: 10.4049/jimmunol.181.6.3784
Rook, A. H. et al. Effects of transforming growth factor beta on the functions of natural killer cells: Depressed cytolytic activity and blunting of interferon responsiveness. J. Immunol. 136, 3916–3920 (1986).
pubmed: 2871107
doi: 10.4049/jimmunol.136.10.3916
Spaggiari, G. M. et al. Mesenchymal stem cells inhibit natural killer-cell proliferation, cytotoxicity, and cytokine production: Role of indoleamine 2,3-dioxygenase and prostaglandin E2. Blood 111, 1327–1333 (2008).
pubmed: 17951526
doi: 10.1182/blood-2007-02-074997
Knudsen, N. H. & Manguso, R. T. Tumor-derived PGE2 gives NK cells a headache. Immunity 53, 1131–1132 (2020).
pubmed: 33326763
doi: 10.1016/j.immuni.2020.11.018
Bonavita, E. et al. Antagonistic inflammatory phenotypes dictate tumor fate and response to immune checkpoint blockade. Immunity 53, 1215-1229.e8 (2020).
pubmed: 33220234
pmcid: 7772804
doi: 10.1016/j.immuni.2020.10.020
Zelenay, S. et al. Cyclooxygenase-dependent tumor growth through evasion of immunity. Cell 162, 1257–1270 (2015).
pubmed: 26343581
pmcid: 4597191
doi: 10.1016/j.cell.2015.08.015
Albini, A. et al. TIMP1 and TIMP2 downregulate TGFβ induced decidual-like phenotype in natural killer cells. Cancers https://doi.org/10.3390/cancers13194955 (2021).
doi: 10.3390/cancers13194955
pubmed: 34638439
pmcid: 8507839
Proudfoot, A. E. I. Chemokine receptors: Multifaceted therapeutic targets. Nat. Rev. Immunol. 2, 106–115 (2002).
pubmed: 11910892
pmcid: 7097668
doi: 10.1038/nri722
Pérez del Río, E. et al. CCL21-loaded 3D hydrogels for T cell expansion and differentiation. Biomaterials 259, 120313 (2020).
pubmed: 32829146
doi: 10.1016/j.biomaterials.2020.120313
Hu, Z., Xu, X. & Wei, H. The adverse impact of tumor microenvironment on NK-cell. Front. Immunol. 12, 633361 (2021).
pubmed: 34177887
pmcid: 8226132
doi: 10.3389/fimmu.2021.633361
Melaiu, O., Lucarini, V., Cifaldi, L. & Fruci, D. Influence of the tumor microenvironment on NK cell function in solid tumors. Front. Immunol. 10, 3038 (2019).
pubmed: 32038612
doi: 10.3389/fimmu.2019.03038
Yang, Y., Chen, L., Zheng, B. & Zhou, S. Metabolic hallmarks of natural killer cells in the tumor microenvironment and implications in cancer immunotherapy. Oncogene 42, 1–10 (2023).
pubmed: 36473909
doi: 10.1038/s41388-022-02562-w
Korde, N. et al. A phase II trial of pan-KIR2D blockade with IPH2101 in smoldering multiple myeloma. Haematologica https://doi.org/10.3324/haematol.2013.103085 (2014).
doi: 10.3324/haematol.2013.103085
pubmed: 25472951
pmcid: 4258744
O’Shea, D., Cawood, T. J., O’Farrelly, C. & Lynch, L. Natural killer cells in obesity: Impaired function and increased susceptibility to the effects of cigarette smoke. PLoS ONE 5, e8660 (2010).
pubmed: 20107494
pmcid: 2801590
doi: 10.1371/journal.pone.0008660
Tobin, L. M. et al. NK cells in childhood obesity are activated, metabolically stressed, and functionally deficient. JCI Insight 2, e94939 (2017).
pubmed: 29263296
pmcid: 5752310
doi: 10.1172/jci.insight.94939
Bähr, I. et al. Impaired natural killer cell subset phenotypes in human obesity. Immunol. Res. 66, 234–244 (2018).
pubmed: 29560551
pmcid: 5899081
doi: 10.1007/s12026-018-8989-4
Viel, S. et al. Alteration of natural killer cell phenotype and function in obese individuals. Clin. Immunol. 177, 12–17 (2017).
pubmed: 26794911
doi: 10.1016/j.clim.2016.01.007
O’Connell, F. et al. Energy metabolism, metabolite, and inflammatory profiles in human ex vivo adipose tissue are influenced by obesity status, metabolic dysfunction, and treatment regimes in patients with oesophageal adenocarcinoma. Cancers (Basel) 15, 1681 (2023).
pubmed: 36980567
doi: 10.3390/cancers15061681
Kavanagh, M. E. et al. Impact of the inflammatory microenvironment on T-cell phenotype in the progression from reflux oesophagitis to Barrett oesophagus and oesophageal adenocarcinoma. Cancer Lett. 370, 117–124 (2016).
pubmed: 26519754
doi: 10.1016/j.canlet.2015.10.019
Wensveen, F. M. et al. NK cells link obesity-induced adipose stress to inflammation and insulin resistance. Nat. Immunol. 16, 376–385 (2015).
pubmed: 25729921
doi: 10.1038/ni.3120
Wensveen, F. M., Valentić, S., Šestan, M., Turk Wensveen, T. & Polić, B. The ‘big bang’ in obese fat: Events initiating obesity-induced adipose tissue inflammation. Eur. J. Immunol. 45, 2446–2456. https://doi.org/10.1002/eji.201545502 (2015).
doi: 10.1002/eji.201545502
pubmed: 26220361
White, G. E. & Greaves, D. R. Fractalkine: A survivor’s guide: Chemokines as antiapoptotic mediators. Arterioscler. Thromb. Vasc. Biol. 32, 589–594 (2012).
pubmed: 22247260
doi: 10.1161/ATVBAHA.111.237412
Hamann, I. et al. Analyses of phenotypic and functional characteristics of CX3CR1-expressing natural killer cells. Immunology 133, 62–73 (2011).
pubmed: 21320123
pmcid: 3088968
doi: 10.1111/j.1365-2567.2011.03409.x
Li, F. et al. CCL5-armed oncolytic virus augments CCR5-engineered NK cell infiltration and antitumor efficiency. J. Immunother. Cancer 8, e000131 (2020).
pubmed: 32098828
pmcid: 7057442
doi: 10.1136/jitc-2019-000131
Zheng, C. et al. In situ modification of the tumor cell surface with immunomodulating nanoparticles for effective suppression of tumor growth in mice. Adv. Mater. 31, 1902542 (2019).
doi: 10.1002/adma.201902542
Peng, D. et al. Epigenetic silencing of TH1-type chemokines shapes tumour immunity and immunotherapy. Nature 527, 249–253 (2015).
pubmed: 26503055
pmcid: 4779053
doi: 10.1038/nature15520
Xing, S. & Ferrari de Andrade, L. NKG2D and MICA/B shedding: A ‘tag game’ between NK cells and malignant cells. Clin. Transl. Immunol. 9, e1230 (2020).
doi: 10.1002/cti2.1230
Power, R., Lowery, M. A., Reynolds, J. V. & Dunne, M. R. The cancer-immune set point in oesophageal cancer. Front. Oncol. 10, 891 (2020).
pubmed: 32582553
pmcid: 7287212
doi: 10.3389/fonc.2020.00891
Doyle, S. L. et al. Establishing computed tomography-defined visceral fat area thresholds for use in obesity-related cancer research. Nutr. Res. 33, 171–179 (2013).
pubmed: 23507222
doi: 10.1016/j.nutres.2012.12.007
Ibidi. Chemotaxis and Migration Tool 2.0.