Immunotherapy response modeling by ex-vivo organ culture for lung cancer.

B7-H1 Antigen / immunology Biomarkers, Tumor / immunology CD4 Antigens / immunology CD8 Antigens / immunology CTLA-4 Antigen / immunology Carcinoma, Non-Small-Cell Lung / immunology Forkhead Transcription Factors / immunology Humans Immunohistochemistry / methods Immunologic Factors / immunology Immunotherapy / methods Interferon-gamma / immunology Lung Neoplasms / immunology Organ Culture Techniques / methods Tumor Microenvironment / immunology
Anti-CTLA4 Anti-PD-L1 Early-stage NSCLC IFNγ Tumor-microenvironment

Journal

Cancer immunology, immunotherapy : CII
ISSN: 1432-0851
Titre abrégé: Cancer Immunol Immunother
Pays: Germany
ID NLM: 8605732

Informations de publication

Date de publication:
Aug 2021
Historique:
received: 13 07 2020
accepted: 09 12 2020
pubmed: 24 1 2021
medline: 27 7 2021
entrez: 23 1 2021
Statut: ppublish

Résumé

One of the major hurdles for the advancement of cancer immunotherapy is lack of robust, accessible experimental models. We aimed to produce an ex-vivo organ culture (EVOC) model of immunotherapy for non-small cell lung cancer (NSCLC). Freshly resected early stage tumors were collected from the operating room, fragmented to clusters < 450 µm and cultured with fetal calf serum and human autologous serum. The resulting EVOC includes cancer epithelial cells within tumor tissue clusters and immune cells. Original tissue features are reflected in the EVOCs. The response to immune checkpoint inhibitors (ICI) was assessed by IFNγ gene induction. Interestingly, IFNγ EVOC induction was numerically higher when anti-CTLA4 was added to anti-PD-L1 treatment, supporting the notion that anti-CTLA4 impacts cancer partly through tumor-resident immune cells. In parallel, immunohistochemistry (IHC) for key immune-related proteins was performed on the formalin-fixed paraffin embedded (FFPE) corresponding tumors. EVOC IFNγ induction by ICI correlated with basal non-induced IFNγ, CD8, CD4 and FOXP3 mRNA levels within EVOCs and with tumor-FFPE-IHC for CD8 and granzyme B. A weaker correlation was seen with tumor-FFPE-IHC for CD3, CD4, CD68, FOXP3 and tumor-PD-L1. Tertiary lymphoid structure density was also correlated with the ICI response. Our study provides novel data about biomarkers that correlate with ICI-induced response of early stage NSCLC. Retention of the microenvironment and minimal addition of exogenous factors suggest this model to reliably represent the original tumor. The cluster-based EVOC model we describe can provide a valuable, yet simple and widely applicable tool for the study of immunotherapy in NSCLC.

Identifiants

DOI: 10.1007/s00262-020-02828-w PMID: 33484295
pubmed: 33484295
doi: 10.1007/s00262-020-02828-w
pii: 10.1007/s00262-020-02828-w
doi:

Substances chimiques

B7-H1 Antigen 0
Biomarkers, Tumor 0
CD4 Antigens 0
CD8 Antigens 0
CTLA-4 Antigen 0
Forkhead Transcription Factors 0
Immunologic Factors 0
Interferon-gamma 82115-62-6

Types de publication

Journal Article

Langues

eng

Sous-ensembles de citation

IM

Pagination

2223-2234

Subventions

Organisme : AstraZeneca,
ID : NCR-15-11358
Organisme : Israel CancerAssociation
ID : 20190081
Organisme : Ministry of Health, State of Israel
ID : 3-14487

Informations de copyright

© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH, DE part of Springer Nature.

Références

Siegel R, Naishadham D, Jemal A (2013) Cancer statistics, 2013. CA Cancer J Clin 63:11–30. https://doi.org/10.3322/caac.21166
doi: 10.3322/caac.21166 pubmed: 23335087
Sznol M, Chen L (2013) Antagonist antibodies to PD-1 and B7–H1 (PD-L1) in the treatment of advanced human cancer. Clin Cancer Res 19:1021–1034. https://doi.org/10.1158/1078-0432.CCR-12-2063
doi: 10.1158/1078-0432.CCR-12-2063 pubmed: 23460533 pmcid: 3702373
Hellmann MD, Rizvi NA, Goldman JW et al (2017) Nivolumab plus ipilimumab as first-line treatment for advanced non-small-cell lung cancer (CheckMate 012): results of an open-label, phase 1, multicohort study. Lancet Oncol 18:31–41. https://doi.org/10.1016/S1470-2045(16)30624-6
doi: 10.1016/S1470-2045(16)30624-6 pubmed: 27932067
Gandhi L, Rodríguez-Abreu D, Gadgeel S et al (2018) Pembrolizumab plus chemotherapy in metastatic non–small-cell lung cancer. N Engl J Med 378:2078–2092. https://doi.org/10.1056/NEJMoa1801005
doi: 10.1056/NEJMoa1801005 pubmed: 29658856
Theelen WSME, Peulen HMU, Lalezari F et al (2019) Effect of pembrolizumab after stereotactic body radiotherapy vs pembrolizumab alone on tumor response in patients with advanced non-small cell lung cancer. JAMA Oncol 5:1276. https://doi.org/10.1001/jamaoncol.2019.1478
doi: 10.1001/jamaoncol.2019.1478 pubmed: 31294749 pmcid: 6624814
Topalian SL, Taube JM, Pardoll DM (2020) Neoadjuvant checkpoint blockade for cancer immunotherapy. Science 367:eaax0182. https://doi.org/10.1126/science.aax0182
doi: 10.1126/science.aax0182 pubmed: 32001626 pmcid: 7789854
Bar J, Moskovits N, Oren M (2010) Involvement of stromal p53 in tumor-stroma interactions. Semin Cell Dev Biol 21:47–54. https://doi.org/10.1016/j.semcdb.2009.11.006
doi: 10.1016/j.semcdb.2009.11.006 pubmed: 19914385
Bhowmick NA, Neilson EG, Moses HL (2004) Stromal fibroblasts in cancer initiation and progression. Nature 432:332–337. https://doi.org/10.1038/nature03096
doi: 10.1038/nature03096 pubmed: 15549095 pmcid: 3050735
Mueller MM, Fusenig NE (2004) Friends or foes—bipolar effects of the tumour stroma in cancer. Nat Rev Cancer 4:839–849. https://doi.org/10.1038/nrc1477
doi: 10.1038/nrc1477 pubmed: 15516957
Aparicio S, Hidalgo M, Kung AL (2015) Examining the utility of patient-derived xenograft mouse models. Nat Rev Cancer 15:311–316. https://doi.org/10.1038/nrc3944
doi: 10.1038/nrc3944 pubmed: 25907221
Lai Y, Wei X, Lin S et al (2017) Current status and perspectives of patient-derived xenograft models in cancer research. J Hematol Oncol 10:106. https://doi.org/10.1186/s13045-017-0470-7
doi: 10.1186/s13045-017-0470-7 pubmed: 28499452 pmcid: 5427553
Behrens D, Rolff J, Hoffmann J (2016) Predictive in vivo models for oncology. Handb Exp Pharmacol 232:203–221. https://doi.org/10.1007/164_2015_29
doi: 10.1007/164_2015_29 pubmed: 26489829
Endo H, Okami J, Okuyama H et al (2013) Spheroid culture of primary lung cancer cells with neuregulin 1/HER3 pathway activation. J Thorac Oncol 8:131–139. https://doi.org/10.1097/JTO.0b013e3182779ccf
doi: 10.1097/JTO.0b013e3182779ccf pubmed: 23328545
Majumder B, Baraneedharan U, Thiyagarajan S et al (2015) Predicting clinical response to anticancer drugs using an ex vivo platform that captures tumour heterogeneity. Nat Commun 6:6169–6183. https://doi.org/10.1038/ncomms7169
doi: 10.1038/ncomms7169 pubmed: 25721094
Karekla E, Liao W-J, Sharp B, Pugh J, Reid H, Quesne JL, Moore D, Pritchard C, MacFarlane M, Pringle JH (2017) Ex vivo explant cultures of non-small cell lung carcinoma enable evaluation of primary tumor responses to anticancer therapy. Cancer Res 77(8):2029–2039. https://doi.org/10.1158/0008-5472.CAN-16-1121
doi: 10.1158/0008-5472.CAN-16-1121 pubmed: 28202521
Kim M, Mun H, Sung CO et al (2019) Patient-derived lung cancer organoids as in vitro cancer models for therapeutic screening. Nat Commun 10:3991–4005. https://doi.org/10.1038/s41467-019-11867-6
doi: 10.1038/s41467-019-11867-6 pubmed: 31488816 pmcid: 6728380
Neal JT, Li X, Zhu J et al (2018) Organoid modeling of the tumor immune microenvironment. Cell 175:1972-1988.e16. https://doi.org/10.1016/j.cell.2018.11.021
doi: 10.1016/j.cell.2018.11.021 pubmed: 30550791 pmcid: 6656687
Jenkins RW, Aref AR, Lizotte PH et al (2018) Ex vivo profiling of PD-1 blockade using organotypic tumor spheroids. Cancer Discov 8:196–215. https://doi.org/10.1158/2159-8290.CD-17-0833
doi: 10.1158/2159-8290.CD-17-0833 pubmed: 29101162
Dijkstra KK, Cattaneo CM, Weeber F et al (2018) Generation of tumor-reactive T cells by co-culture of peripheral blood lymphocytes and tumor organoids. Cell 174:1586-1598.e12. https://doi.org/10.1016/j.cell.2018.07.009
doi: 10.1016/j.cell.2018.07.009 pubmed: 30100188 pmcid: 6558289
Sachs N, Papaspyropoulos A, Zomer-van Ommen DD et al (2019) Long-term expanding human airway organoids for disease modeling. EMBO J. https://doi.org/10.15252/embj.2018100300
doi: 10.15252/embj.2018100300 pubmed: 30643021 pmcid: 6376275
Stewart R, Morrow M, Hammond SA et al (2015) Identification and characterization of MEDI4736, an antagonistic Anti-PD-L1 monoclonal antibody. Cancer Immunol Res 3:1052–1062. https://doi.org/10.1158/2326-6066.CIR-14-0191
doi: 10.1158/2326-6066.CIR-14-0191 pubmed: 25943534
Centanni M, Moes DJAR, Trocóniz IF et al (2019) Clinical pharmacokinetics and pharmacodynamics of immune checkpoint inhibitors. Clin Pharmacokinet 58:835–857. https://doi.org/10.1007/s40262-019-00748-2
doi: 10.1007/s40262-019-00748-2 pubmed: 30815848 pmcid: 6584248
Neuman T, London M, Kania-Almog J et al (2016) A harmonization study for the use of 22C3 PD-L1 immunohistochemical staining on ventana’s platform. J Thorac Oncol 11:1863–1868. https://doi.org/10.1016/j.jtho.2016.08.146
doi: 10.1016/j.jtho.2016.08.146 pubmed: 27664534
Bellmunt J, Mullane SA, Werner L et al (2015) Association of PD-L1 expression on tumor-infiltrating mononuclear cells and overall survival in patients with urothelial carcinoma. Ann Oncol 26:812–817. https://doi.org/10.1093/annonc/mdv009
doi: 10.1093/annonc/mdv009 pubmed: 25600565
Ujiie H, Kadota K, Chaft JE et al (2015) Solid predominant histologic subtype in resected stage I lung adenocarcinoma is an independent predictor of early, extrathoracic, multisite recurrence and of poor postrecurrence survival. J Clin Oncol 33:2877–2884. https://doi.org/10.1200/JCO.2015.60.9818
doi: 10.1200/JCO.2015.60.9818 pubmed: 26261257 pmcid: 4554749
Hung JJ, Yeh YC, Wu YC et al (2017) Prognostic factors in completely resected node-negative lung adenocarcinoma of 3 cm or smaller. J Thorac Oncol 12:1824–1833. https://doi.org/10.1016/j.jtho.2017.07.009
doi: 10.1016/j.jtho.2017.07.009 pubmed: 28739441
Ayers M, Lunceford J, Nebozhyn M et al (2017) IFNγ-γ-related mRNA profile predicts clinical response to PD-1 blockade. J Clin Invest 127:2930–2940. https://doi.org/10.1172/JCI91190
doi: 10.1172/JCI91190 pubmed: 28650338 pmcid: 5531419
Fehrenbacher L, Spira A, Ballinger M et al (2016) Atezolizumab versus docetaxel for patients with previously treated non-small-cell lung cancer (POPLAR): a multicentre, open-label, phase 2 randomised controlled trial. Lancet 387:1837–1846. https://doi.org/10.1016/S0140-6736(16)00587-0
doi: 10.1016/S0140-6736(16)00587-0 pubmed: 26970723
Blons H, Garinet S, Laurent-Puig P, Oudart JB (2019) Molecular markers and prediction of response to immunotherapy in non-small cell lung cancer, an update. J Thorac Dis 11:S25–S36. https://doi.org/10.21037/jtd.2018.12.48
doi: 10.21037/jtd.2018.12.48 pubmed: 30775025 pmcid: 6353739
Sautès-Fridman C, Petitprez F, Calderaro J, Fridman WH (2019) Tertiary lymphoid structures in the era of cancer immunotherapy. Nat Rev Cancer 19:307–325. https://doi.org/10.1038/s41568-019-0144-6
doi: 10.1038/s41568-019-0144-6 pubmed: 31092904
Helmink BA, Reddy SM, Gao J et al (2020) B cells and tertiary lymphoid structures promote immunotherapy response. Nature 577:549–555. https://doi.org/10.1038/s41586-019-1922-8
doi: 10.1038/s41586-019-1922-8 pubmed: 31942075
Wei SC, Duffy CR, Allison JP (2018) Fundamental mechanisms of immune checkpoint blockade therapy. Cancer Discov 8:1069–1086. https://doi.org/10.1158/2159-8290.CD-18-0367
doi: 10.1158/2159-8290.CD-18-0367 pubmed: 30115704
Silva MA, Ryall KA, Wilm C et al (2018) PD-L1 immunostaining scoring for non-small cell lung cancer based on immunosurveillance parameters. PLoS ONE 13:e0196464. https://doi.org/10.1371/journal.pone.0196464
doi: 10.1371/journal.pone.0196464 pubmed: 29874226 pmcid: 5991369
Donnem T, Hald SM, Paulsen E-E et al (2015) Stromal CD8 + T-cell density—A promising supplement to TNM staging in non-small cell lung cancer. Clin Cancer Res 21:2635–2643. https://doi.org/10.1158/1078-0432.CCR-14-1905
doi: 10.1158/1078-0432.CCR-14-1905 pubmed: 25680376
Socinski MA, Jotte RM, Cappuzzo F et al (2018) Atezolizumab for first-line treatment of metastatic nonsquamous NSCLC. N Engl J Med 378:2288–2301. https://doi.org/10.1056/NEJMoa1716948
doi: 10.1056/NEJMoa1716948 pubmed: 29863955
Lund JM, Hsing L, Pham TT, Rudensky AY (2008) Coordination of early protective immunity to viral infection by regulatory T cells. Science 320:1220–1224. https://doi.org/10.1126/science.1155209
doi: 10.1126/science.1155209 pubmed: 18436744 pmcid: 2519146
Ribas A, Comin-Anduix B, Economou JS et al (2009) Intratumoral immune cell infiltrates, FoxP3, and indoleamine 2,3-dioxygenase in patients with melanoma undergoing CTLA4 blockade. Clin Cancer Res 15:390–399. https://doi.org/10.1158/1078-0432.CCR-08-0783
doi: 10.1158/1078-0432.CCR-08-0783 pubmed: 19118070
Hamid O, Schmidt H, Nissan A et al (2011) A prospective phase II trial exploring the association between tumor microenvironment biomarkers and clinical activity of ipilimumab in advanced melanoma. J Transl Med 9:204. https://doi.org/10.1186/1479-5876-9-204
doi: 10.1186/1479-5876-9-204 pubmed: 22123319 pmcid: 3239318
Allan SE, Crome SQ, Crellin NK et al (2007) Activation-induced FOXP3 in human T effector cells does not suppress proliferation or cytokine production. Int Immunol 19:345–354. https://doi.org/10.1093/intimm/dxm014
doi: 10.1093/intimm/dxm014 pubmed: 17329235
Rhodin KE, Rucker AJ, Ready NE et al (2020) The immunotherapeutic landscape in non–small cell lung cancer and its surgical horizons. J Thorac Cardiovasc Surg 159:1616–1623. https://doi.org/10.1016/j.jtcvs.2019.08.138
doi: 10.1016/j.jtcvs.2019.08.138 pubmed: 31836182
Hellmann MD, Paz-Ares L, Bernabe Caro R et al (2019) Nivolumab plus ipilimumab in advanced non–small-cell lung cancer. N Engl J Med 381:2020–2031. https://doi.org/10.1056/NEJMoa1910231
doi: 10.1056/NEJMoa1910231 pubmed: 31562796
Sato T, Stange DE, Ferrante M et al (2011) Long-term expansion of epithelial organoids from human colon, adenoma, adenocarcinoma, and barrett’s epithelium. Gastroenterology 141:1762–1772. https://doi.org/10.1053/j.gastro.2011.07.050
doi: 10.1053/j.gastro.2011.07.050 pubmed: 21889923
Govindan R, Szczesna A, Ahn MJ et al (2017) Phase III trial of ipilimumab combined with paclitaxel and carboplatin in advanced squamous non–small-cell lung cancer. J Clin Oncol 35:3449–3457. https://doi.org/10.1200/JCO.2016.71.7629
doi: 10.1200/JCO.2016.71.7629 pubmed: 28854067

Auteurs

Iris Kamer (I)

Institute of Oncology, Sheba Medical Center, Tel Hashomer, 52620000, Ramat Gan, Israel.

Elizabeta Bab-Dinitz (E)

Institute of Oncology, Sheba Medical Center, Tel Hashomer, 52620000, Ramat Gan, Israel.

Oranit Zadok (O)

Institute of Oncology, Sheba Medical Center, Tel Hashomer, 52620000, Ramat Gan, Israel.

Efrat Ofek (E)

Pathology Department, Sheba Medical Center, Ramat Gan, Israel.

Teodor Gottfried (T)

Institute of Oncology, Sheba Medical Center, Tel Hashomer, 52620000, Ramat Gan, Israel.

Inbal Daniel-Meshulam (I)

Institute of Oncology, Sheba Medical Center, Tel Hashomer, 52620000, Ramat Gan, Israel.

Goni Hout-Siloni (G)

Pathology Department, Sheba Medical Center, Ramat Gan, Israel.

Alon Ben Nun (A)

Thoracic Surgery Department, Sheba Medical Center, Ramat Gan, Israel.
Affiliated with Sackler School of Medicine, Tel-Aviv University, Tel-Aviv, Israel.
Thoracic Surgery Department, Assuta Medical Center, Tel Aviv, Israel.

Iris Barshack (I)

Pathology Department, Sheba Medical Center, Ramat Gan, Israel.
Affiliated with Sackler School of Medicine, Tel-Aviv University, Tel-Aviv, Israel.

Amir Onn (A)

Pulmonology Institute, Sheba Medical Center, Ramat Gan, Israel.
Affiliated with Sackler School of Medicine, Tel-Aviv University, Tel-Aviv, Israel.

Jair Bar (J)

Institute of Oncology, Sheba Medical Center, Tel Hashomer, 52620000, Ramat Gan, Israel. Bar.jair@gmail.com.
Affiliated with Sackler School of Medicine, Tel-Aviv University, Tel-Aviv, Israel. Bar.jair@gmail.com.
ORCID: 0000-0002-1224-3646

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Classifications MeSH

questionsmedicales.fr › Facteurs biologiques › Protéines et peptides de signalisation intercellulaire › Antigènes B7 › Antigène CD274 › Immunotherapy response modeling by ex-vivo...
questionsmedicales.fr › Facteurs biologiques › Marqueurs biologiques › Marqueurs biologiques tumoraux › Immunotherapy response modeling by ex-vivo...
questionsmedicales.fr › Facteurs biologiques › Marqueurs biologiques › Antigènes de différenciation › Antigènes de différenciation des lymphocytes T › Antigènes CD4 › Immunotherapy response modeling by ex-vivo...
questionsmedicales.fr › Facteurs biologiques › Marqueurs biologiques › Antigènes de différenciation › Antigènes de différenciation des lymphocytes T › Antigènes CD8 › Immunotherapy response modeling by ex-vivo...
questionsmedicales.fr › Facteurs biologiques › Marqueurs biologiques › Antigènes de différenciation › Antigènes de différenciation des lymphocytes T › Antigène CTLA-4 › Immunotherapy response modeling by ex-vivo...
questionsmedicales.fr › Maladies de l'appareil respiratoire › Tumeurs de l'appareil respiratoire › Tumeurs du poumon › Tumeurs des bronches › Carcinome bronchogénique › Carcinome pulmonaire non à petites cellules › Immunotherapy response modeling by ex-vivo...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Facteurs de transcription › Facteurs de transcription à motif hélice ailée › Facteurs de transcription Forkhead › Immunotherapy response modeling by ex-vivo...
questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Primates › Haplorhini › Catarrhini › Hominidae › Humains › Immunotherapy response modeling by ex-vivo...
questionsmedicales.fr › Disciplines des sciences naturelles › Chimie › Biochimie › Immunohistochimie › Immunotherapy response modeling by ex-vivo...
questionsmedicales.fr › Actions chimiques et utilisations › Actions pharmacologiques › Effets physiologiques des médicaments › Facteurs immunologiques › Immunotherapy response modeling by ex-vivo...
questionsmedicales.fr › Thérapeutique › Biothérapie › Immunothérapie › Immunotherapy response modeling by ex-vivo...
questionsmedicales.fr › Facteurs biologiques › Protéines et peptides de signalisation intercellulaire › Cytokines › Lymphokines › Facteurs d'activation des macrophages › Interféron gamma › Immunotherapy response modeling by ex-vivo...
questionsmedicales.fr › Maladies de l'appareil respiratoire › Tumeurs de l'appareil respiratoire › Tumeurs du poumon › Immunotherapy response modeling by ex-vivo...
questionsmedicales.fr › Techniques d'investigation › Techniques in vitro › Techniques de culture › Techniques de culture d'organes › Immunotherapy response modeling by ex-vivo...
questionsmedicales.fr › Phénomènes physiologiques cellulaires › Microenvironnement cellulaire › Microenvironnement tumoral › Immunotherapy response modeling by ex-vivo...