Nutrient deprivation and hypoxia alter T cell immune checkpoint expression: potential impact for immunotherapy.
Glucose deprivation
Hypoxia
Immune checkpoints
Oesophageal adenocarcinoma
Tumour microenvironment
Journal
Journal of cancer research and clinical oncology
ISSN: 1432-1335
Titre abrégé: J Cancer Res Clin Oncol
Pays: Germany
ID NLM: 7902060
Informations de publication
Date de publication:
Jul 2023
Jul 2023
Historique:
received:
17
08
2022
accepted:
18
10
2022
medline:
19
7
2023
pubmed:
30
11
2022
entrez:
29
11
2022
Statut:
ppublish
Résumé
Use of immune checkpoint blockade to enhance T cell-mediated immunity within the hostile tumour microenvironment (TME) is an attractive approach in oesophageal adenocarcinoma (OAC). This study explored the effects of the hostile TME, including nutrient deprivation and hypoxia, on immune checkpoint (IC) expression and T cell phenotypes, and the potential use of nivolumab to enhance T cell function under such conditions. ICs were upregulated on stromal immune cells within the tumour including PD-L2, CTLA-4 and TIGIT. OAC patient-derived PBMCs co-cultured with OE33 OAC cells upregulated LAG-3 and downregulated the co-stimulatory marker CD27 on T cells, highlighting the direct immunosuppressive effects of tumour cells on T cells. Hypoxia and nutrient deprivation altered the secretome of OAC patient-derived PBMCs, which induced upregulation of PD-L1 and PD-L2 on OE33 OAC cells thus enhancing an immune-resistant phenotype. Importantly, culturing OAC patient-derived PBMCs under dual hypoxia and glucose deprivation, reflective of the conditions within the hostile TME, upregulated an array of ICs on the surface of T cells including PD-1, CTLA-4, A2aR, PD-L1 and PD-L2 and decreased expression of IFN-γ by T cells. Addition of nivolumab under these hostile conditions decreased the production of pro-tumorigenic cytokine IL-10. Collectively, these findings highlight the immunosuppressive crosstalk between tumour cells and T cells within the OAC TME. The ability of nivolumab to suppress pro-tumorigenic T cell phenotypes within the hostile TME supports a rationale for the use of immune checkpoint blockade to promote anti-tumour immunity in OAC. Study schematic: (A) IC expression profiles were assessed on CD45 (A) TIGIT, CTLA-4 and PD-L2 were upregulated on CD45
Identifiants
pubmed: 36445478
doi: 10.1007/s00432-022-04440-0
pii: 10.1007/s00432-022-04440-0
pmc: PMC10349772
doi:
Substances chimiques
CTLA-4 Antigen
0
B7-H1 Antigen
0
Interleukin-10
130068-27-8
Nivolumab
31YO63LBSN
Immune Checkpoint Inhibitors
0
Interleukin-2
0
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
5377-5395Subventions
Organisme : Irish Research Council for Science, Engineering and Technology
ID : GOIPG/2017/1659
Informations de copyright
© 2022. The Author(s).
Références
Ascierto PA et al (2017) Efficacy of BMS-986016, a monoclonal antibody that targets lymphocyte activation gene-3 (LAG-3), in combination with nivolumab in pts with melanoma who progressed during prior anti–PD-1/PD-L1 therapy (mel prior IO) in all-comer and biomarker-enrich. Ann Oncol 28:v611–v612
Blackburn SD et al (2009) Coregulation of CD8+ T cell exhaustion by multiple inhibitory receptors during chronic viral infection. Nat Immunol 10:29–37
pubmed: 19043418
Braun DA et al (2021) Beyond conventional immune-checkpoint inhibition—novel immunotherapies for renal cell carcinoma. Nat Rev Clin Oncol 18:199–214
pubmed: 33437048
pmcid: 8317018
Camisaschi C et al (2010) LAG-3 expression defines a subset of CD4+CD25highFoxp3+ regulatory T cells that are expanded at tumor sites. J Immunol 184:6545–6551
pubmed: 20421648
Cham CM, Driessens G, O’Keefe JP, Gajewski TF (2008) Glucose deprivation inhibits multiple key gene expression events and effector functions in CD8+ T cells. Eur J Immunol 38:2438–2450
pubmed: 18792400
pmcid: 3008428
Chang C-H et al (2015) Metabolic competition in the tumor microenvironment is a driver of cancer progression. Cell 162:1229–1241
pubmed: 26321679
pmcid: 4864363
Chen C et al (2019) Efficacy and safety of immune checkpoint inhibitors in advanced gastric or gastroesophageal junction cancer: a systematic review and meta-analysis. Oncoimmunology 8:e1581547
pubmed: 31069144
pmcid: 6492970
Cohen S, Danzaki K, MacIver NJ (2017) Nutritional effects on T-cell immunometabolism. Eur J Immunol 47:225–235
pubmed: 28054344
pmcid: 5342627
Davern M, Lysaght J (2020) Cooperation between chemotherapy and immunotherapy in gastroesophageal cancers. Cancer Lett. https://doi.org/10.1016/j.canlet.2020.09.014
doi: 10.1016/j.canlet.2020.09.014
pubmed: 33347908
Davern M et al (2021a) The tumour immune microenvironment in oesophageal cancer. Br J Cancer. https://doi.org/10.1038/s41416-021-01331-y
doi: 10.1038/s41416-021-01331-y
pubmed: 33903730
pmcid: 8368180
Davern M et al (2021b) Chemotherapy regimens induce inhibitory immune checkpoint protein expression on stem-like and senescent-like oesophageal adenocarcinoma cells. Transl Oncol 14:101062
pubmed: 33765543
pmcid: 8008239
DePeaux K, Delgoffe GM (2021) Metabolic barriers to cancer immunotherapy. Nat Rev Immunol. https://doi.org/10.1038/s41577-021-00541-y
doi: 10.1038/s41577-021-00541-y
pubmed: 33927375
pmcid: 8553800
Donlon NE et al (2020) Adverse biology in adenocarcinoma of the esophagus and esophagogastric junction impacts survival and response to neoadjuvant therapy independent of anatomic subtype. Ann Surg 272:814–819
pubmed: 32657924
Elyaman W et al (2008) Distinct functions of autoreactive memory and effector CD4
pubmed: 18583313
pmcid: 2475778
Facciabene A et al (2011) Tumour hypoxia promotes tolerance and angiogenesis via CCL28 and Treg cells. Nature 475:226–230
pubmed: 21753853
Gajewski TF, Meng Y, Harlin H (2006) Immune suppression in the tumor microenvironment. J Immunother 29:233–240
pubmed: 16699366
Gandhi MK et al (2006) Expression of LAG-3 by tumor-infiltrating lymphocytes is coincident with the suppression of latent membrane antigen–specific CD8+ T-cell function in Hodgkin lymphoma patients. Blood 108:2280–2289
pubmed: 16757686
Giannone G et al (2020) Immuno-metabolism and microenvironment in cancer: key players for immunotherapy. Int J Mol Sci 21:4414
pubmed: 32575899
pmcid: 7352562
Grosso JF et al (2007) LAG-3 regulates CD8+ T cell accumulation and effector function in murine self- and tumor-tolerance systems. J Clin Invest 117:3383–3392
pubmed: 17932562
pmcid: 2000807
Guo C et al (2019) Chapter Four—Immunometabolism: a new target for improving cancer immunotherapy. In: Wang X-Y, Fisher PBBT-A (eds) Immunotherapy of cancer, vol 143. Academic Press, New York, pp 195–253
Hong DS et al (2018) Phase I/II study of LAG525 ± spartalizumab (PDR001) in patients (pts) with advanced malignancies. J Clin Oncol 36:3012
Kazemi MH et al (2021) Immune and metabolic checkpoints blockade: dual wielding against tumors. Int Immunopharmacol 94:107461
pubmed: 33592403
Kelly RJ et al (2021) Adjuvant nivolumab in resected esophageal or gastroesophageal junction cancer. N Engl J Med 384:1191–1203
pubmed: 33789008
Kim EH, Neldner B, Gui J, Craig RW, Suresh M (2016) Mcl-1 regulates effector and memory CD8 T-cell differentiation during acute viral infection. Virology 490:75–82
pubmed: 26855329
Kim S et al (2019) Programmed cell death ligand-1-mediated enhancement of hexokinase 2 expression is inversely related to T-cell effector gene expression in non-small-cell lung cancer. J Exp Clin Cancer Res 38:462
pubmed: 31718692
pmcid: 6852926
King R et al (2021) Hypoxia and its impact on the tumour microenvironment of gastroesophageal cancers. World J Gastrointest Oncol 13:312–331
pubmed: 34040696
pmcid: 8131902
Lee JB, Ha S-J, Kim HR (2021) Clinical insights into novel immune checkpoint inhibitors. Front Pharmacol 12:1074
Li Y, Wu Y, Hu Y (2021) Metabolites in the tumor microenvironment reprogram functions of immune effector cells through epigenetic modifications. Front Immunol 12:1017
Lin R et al (2020) Fatty acid oxidation controls CD8
pubmed: 32075801
Ma S-R et al (2017) Blockade of adenosine A2A receptor enhances CD8+ T cells response and decreases regulatory T cells in head and neck squamous cell carcinoma. Mol Cancer 16:99
pubmed: 28592285
pmcid: 5461710
MacPherson S, Kilgour M, Lum JJ (2018) Understanding lymphocyte metabolism for use in cancer immunotherapy. FEBS J 285:2567–2578
pubmed: 29611301
Maruhashi T, Sugiura D, Okazaki I, Okazaki T (2020) LAG-3: from molecular functions to clinical applications. J Immunother Cancer 8:e001014
pubmed: 32929051
pmcid: 7488795
Mockler MB, Conroy MJ, Lysaght J (2014) Targeting T cell immunometabolism for cancer immunotherapy; understanding the impact of the tumor microenvironment. Front Oncol 4:107
pubmed: 24904823
pmcid: 4032940
Mondanelli G et al (2017) A relay pathway between arginine and tryptophan metabolism confers immunosuppressive properties on dendritic cells. Immunity 46:233–244
pubmed: 28214225
pmcid: 5337620
Munn DH, Bronte V (2016) Immune suppressive mechanisms in the tumor microenvironment. Curr Opin Immunol 39:1–6
pubmed: 26609943
Muz B, de la Puente P, Azab F, Azab AK (2015) The role of hypoxia in cancer progression, angiogenesis, metastasis, and resistance to therapy. Hypoxia. https://doi.org/10.2147/hp.s93413
doi: 10.2147/hp.s93413
pubmed: 27774485
pmcid: 5045092
O’Malley G et al (2018) Stromal cell PD-L1 inhibits CD8
pubmed: 30228206
Park H-R et al (2004) Effect on tumor cells of blocking survival response to glucose deprivation. JNCI J Natl Cancer Inst 96:1300–1310
pubmed: 15339968
Patsoukis N et al (2015) PD-1 alters T-cell metabolic reprogramming by inhibiting glycolysis and promoting lipolysis and fatty acid oxidation. Nat Commun 6:6692
pubmed: 25809635
Pera M, Manterola C, Vidal O, Grande L (2005) Epidemiology of esophageal adenocarcinoma. J Surg Oncol 92:151–159
pubmed: 16299786
Power R, Lowery MA, Reynolds JV, Dunne MR (2020) The cancer-immune set point in oesophageal cancer. Front Oncol 10:891
pubmed: 32582553
pmcid: 7287212
Raud B et al (2018) Etomoxir actions on regulatory and memory T cells are independent of Cpt1a-mediated fatty acid oxidation. Cell Metab 28:504-515.e7
pubmed: 30043753
pmcid: 6747686
Romio M et al (2011) Extracellular purine metabolism and signaling of CD73-derived adenosine in murine Treg and Teff cells. Am J Physiol Physiol 301:C530–C539
Sharma A et al (2019) Anti-CTLA-4 immunotherapy does not deplete FOXP3+ regulatory T cells (Tregs) in human cancers. Clin Cancer Res 25:1233–1238
pubmed: 30054281
Singer K, Cheng W-C, Kreutz M, Ho P-C, Siska PJ (2018) Immunometabolism in cancer at a glance. Dis Model Mech 11:dmm034272
pubmed: 30076128
pmcid: 6124550
Smyth E, Thuss-Patience PC (2018) Immune checkpoint inhibition in gastro-oesophageal cancer. Oncol Res Treat 41:272–280
pubmed: 29705787
Sobhani N et al (2021) CTLA-4 in regulatory T cells for cancer immunotherapy. Cancers 13
Thompson ED et al (2017) Patterns of PD-L1 expression and CD8 T cell infiltration in gastric adenocarcinomas and associated immune stroma. Gut 66:794–801
pubmed: 26801886
Toor SM, Sasidharan Nair V, Decock J, Elkord E (2020) Immune checkpoints in the tumor microenvironment. Semin Cancer Biol 65:1–12
pubmed: 31265893
Villa M, O’Sullivan D, Pearce EL (2021) Glucose makes T
pubmed: 33848476
Warburg O, Wind F, Negelein E (1927) The metabolism of tumors in the body. J Gen Physiol 8:519–530
pubmed: 19872213
pmcid: 2140820
Yin Z et al (2019) Targeting T cell metabolism in the tumor microenvironment: an anti-cancer therapeutic strategy. J Exp Clin Cancer Res 38:403
pubmed: 31519198
pmcid: 6743108
Yoshihara K et al (2013) Inferring tumour purity and stromal and immune cell admixture from expression data. Nat Commun 4:2612
pubmed: 24113773