Blockade of IL-1α and IL-1β signaling by the anti-IL1RAP antibody nadunolimab (CAN04) mediates synergistic anti-tumor efficacy with chemotherapy.
Cancer
Chemotherapy
IL-1α
IL-1β
Interleukin-1 receptor accessory protein
Journal
Cancer immunology, immunotherapy : CII
ISSN: 1432-0851
Titre abrégé: Cancer Immunol Immunother
Pays: Germany
ID NLM: 8605732
Informations de publication
Date de publication:
Mar 2023
Mar 2023
Historique:
received:
24
05
2022
accepted:
12
08
2022
pubmed:
30
8
2022
medline:
25
2
2023
entrez:
29
8
2022
Statut:
ppublish
Résumé
IL-1α and IL-1β are both involved in several aspects of tumor biology, including tumor initiation, progression, metastasis, and not least in resistance to various therapies. IL-1α can function as an alarmin to signal cellular stress, and acts to induce downstream events, including production of IL-1β, to amplify the signal. Both IL-1α and IL-1β act through the same receptor complex, IL-1R1-IL1RAP, to mediate signal transduction. IL1RAP is expressed on tumor cells and in the tumor microenvironment by for example CAF, macrophages and endothelial cells. The anti-IL1RAP antibody nadunolimab (CAN04) inhibits both IL-1α and IL-1β signaling and induces ADCC of IL1RAP-expressing tumor cells. As both IL-1α and IL-1β mediate chemoresistance, the aim of this study was to explore the potential synergy between nadunolimab and chemotherapy. This was performed using the NSCLC PDX model LU2503 and the syngeneic MC38 model, in addition to in vitro cell line experiments. We show that chemotherapy induces expression and release of IL-1α from tumor cells and production of IL-1β-converting enzyme, ICE, in the tumor stroma. IL-1α is also demonstrated to act on stromal cells to further induce the secretion of IL-1β, an effect disrupted by nadunolimab. Nadunolimab, and its surrogate antibody, synergize with platinum-based as well as non-platinum-based chemotherapy to induce potent anti-tumor effects, while blockade of only IL-1β signaling by anti-IL-1β antibody does not achieve this effect. In conclusion, blockade of IL1RAP with nadunolimab reduces IL-1-induced chemoresistance of tumors.
Identifiants
pubmed: 36036818
doi: 10.1007/s00262-022-03277-3
pii: 10.1007/s00262-022-03277-3
doi:
Substances chimiques
Interleukin-1beta
0
Antineoplastic Agents
0
Antibodies, Monoclonal
0
Caspase 1
EC 3.4.22.36
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
667-678Informations de copyright
© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.
Références
Dinarello CA (2009) Immunological and inflammatory functions of the interleukin-1 family. Annu Rev Immunol 27:519–550. https://doi.org/10.1146/annurev.immunol.021908.132612
doi: 10.1146/annurev.immunol.021908.132612
pubmed: 19302047
Korherr C, Hofmeister R, Wesche H, Falk W (1997) A critical role for interleukin-1 receptor accessory protein in interleukin-1 signaling. Eur J Immunol 27:262–267. https://doi.org/10.1002/eji.1830270139
doi: 10.1002/eji.1830270139
pubmed: 9022028
Wesche H, Korherr C, Kracht M, Falk W, Resch K, Martin MU (1997) The interleukin-1 receptor accessory protein (IL-1RAcP) is essential for IL-1-induced activation of interleukin-1 receptor-associated kinase (IRAK) and stress-activated protein kinases (SAP kinases). J Biol Chem 272:7727–7731. https://doi.org/10.1074/jbc.272.12.7727
doi: 10.1074/jbc.272.12.7727
pubmed: 9065432
Kim B, Lee Y, Kim E, Kwak A, Ryoo S, Bae SH, Azam T, Kim S, Dinarello CA (2013) The interleukin-1alpha precursor is biologically active and is likely a key alarmin in the IL-1 family of cytokines. Front Immunol 4:391. https://doi.org/10.3389/fimmu.2013.00391
doi: 10.3389/fimmu.2013.00391
pubmed: 24312098
pmcid: 3834611
Howard AD, Kostura MJ, Thornberry N et al (1991) IL-1-converting enzyme requires aspartic acid residues for processing of the IL-1 beta precursor at two distinct sites and does not cleave 31-kDa IL-1 alpha. J Immunol 147:2964–2969
doi: 10.4049/jimmunol.147.9.2964
pubmed: 1919001
Baker KJ, Houston A, Brint E (2019) IL-1 family members in cancer; two sides to every story. Front Immunol 10:1197. https://doi.org/10.3389/fimmu.2019.01197
doi: 10.3389/fimmu.2019.01197
pubmed: 31231372
pmcid: 6567883
Gelfo V, Romaniello D, Mazzeschi M, Sgarzi M, Grilli G, Morselli A, Manzan B, Rihawi K, Lauriola M (2020) Roles of IL-1 in Cancer: From Tumor Progression to Resistance to Targeted Therapies. Int J Mol Sci. https://doi.org/10.3390/ijms21176009
doi: 10.3390/ijms21176009
pubmed: 32825489
pmcid: 7503335
Ridker PM, MacFadyen JG, Thuren T, Everett BM, Libby P, Glynn RJ, Group CT (2017) Effect of interleukin-1beta inhibition with canakinumab on incident lung cancer in patients with atherosclerosis: exploratory results from a randomised, double-blind, placebo-controlled trial. Lancet 390:1833–1842. https://doi.org/10.1016/S0140-6736(17)32247-X
doi: 10.1016/S0140-6736(17)32247-X
pubmed: 28855077
Paz-Ares L, Goto Y, Lim WDT et al (2021) 1194MO Canakinumab (CAN) + docetaxel (DTX) for the second- or third-line (2/3L) treatment of advanced non-small cell lung cancer (NSCLC): CANOPY-2 phase III results. Ann Oncol 32:S953–S954. https://doi.org/10.1016/j.annonc.2021.08.1799
doi: 10.1016/j.annonc.2021.08.1799
Di Paolo NC, Shayakhmetov DM (2016) Interleukin 1alpha and the inflammatory process. Nat Immunol 17:906–913. https://doi.org/10.1038/ni.3503
doi: 10.1038/ni.3503
pubmed: 27434011
pmcid: 5152572
Chiu JW, Binte Hanafi Z, Chew LCY, Mei Y, Liu H (2021) IL-1alpha processing, signaling and its role in cancer progression. Cells. https://doi.org/10.3390/cells10010092
doi: 10.3390/cells10010092
pubmed: 35011683
pmcid: 8749990
Jung DW, Che ZM, Kim J, Kim K, Kim KY, Williams D, Kim J (2010) Tumor-stromal crosstalk in invasion of oral squamous cell carcinoma: a pivotal role of CCL7. Int J Cancer 127:332–344. https://doi.org/10.1002/ijc.25060
doi: 10.1002/ijc.25060
pubmed: 19937793
Tjomsland V, Spangeus A, Valila J et al (2011) Interleukin 1alpha sustains the expression of inflammatory factors in human pancreatic cancer microenvironment by targeting cancer-associated fibroblasts. Neoplasia 13:664–675. https://doi.org/10.1593/neo.11332
doi: 10.1593/neo.11332
pubmed: 21847358
pmcid: 3156657
Bae JY, Kim EK, Yang DH, Zhang X, Park YJ, Lee DY, Che CM, Kim J (2014) Reciprocal interaction between carcinoma-associated fibroblasts and squamous carcinoma cells through interleukin-1alpha induces cancer progression. Neoplasia 16:928–938. https://doi.org/10.1016/j.neo.2014.09.003
doi: 10.1016/j.neo.2014.09.003
pubmed: 25425967
pmcid: 4240921
Sass SN, Ramsey KD, Egan SM, Wang J, Cortes Gomez E, Gollnick SO (2018) Tumor-associated myeloid cells promote tumorigenesis of non-tumorigenic human and murine prostatic epithelial cell lines. Cancer Immunol Immunother 67:873–883. https://doi.org/10.1007/s00262-018-2143-y
doi: 10.1007/s00262-018-2143-y
pubmed: 29502208
pmcid: 5951898
Xu D, Matsuo Y, Ma J, Koide S, Ochi N, Yasuda A, Funahashi H, Okada Y, Takeyama H (2010) Cancer cell-derived IL-1alpha promotes HGF secretion by stromal cells and enhances metastatic potential in pancreatic cancer cells. J Surg Oncol 102:469–477. https://doi.org/10.1002/jso.21530
doi: 10.1002/jso.21530
pubmed: 20872950
Zhuang Z, Ju HQ, Aguilar M et al (2016) IL1 receptor antagonist inhibits pancreatic cancer growth by abrogating NF-kappaB activation. Clin Cancer Res 22:1432–1444. https://doi.org/10.1158/1078-0432.CCR-14-3382
doi: 10.1158/1078-0432.CCR-14-3382
pubmed: 26500238
Liu S, Lee JS, Jie C, Park MH, Iwakura Y, Patel Y, Soni M, Reisman D, Chen H (2018) HER2 overexpression triggers an IL1alpha proinflammatory circuit to drive tumorigenesis and promote chemotherapy resistance. Cancer Res 78:2040–2051. https://doi.org/10.1158/0008-5472.CAN-17-2761
doi: 10.1158/0008-5472.CAN-17-2761
pubmed: 29382706
pmcid: 5899630
Chung AW, Kozielski AJ, Qian W, Zhou J, Anselme AC, Chan AA, Pan PY, Lee DJ, Chang JC (2022) Tocilizumab overcomes chemotherapy resistance in mesenchymal stem-like breast cancer by negating autocrine IL-1A induction of IL-6. NPJ Breast Cancer 8:30. https://doi.org/10.1038/s41523-021-00371-0
doi: 10.1038/s41523-021-00371-0
pubmed: 35260569
pmcid: 8904846
Bruchard M, Mignot G, Derangere V et al (2013) Chemotherapy-triggered cathepsin B release in myeloid-derived suppressor cells activates the Nlrp3 inflammasome and promotes tumor growth. Nat Med 19:57–64. https://doi.org/10.1038/nm.2999
doi: 10.1038/nm.2999
pubmed: 23202296
Zhang D, Li L, Jiang H et al (2018) Tumor-stroma IL1beta-IRAK4 feedforward circuitry drives tumor fibrosis, chemoresistance, and poor prognosis in pancreatic cancer. Cancer Res 78:1700–1712. https://doi.org/10.1158/0008-5472.CAN-17-1366
doi: 10.1158/0008-5472.CAN-17-1366
pubmed: 29363544
pmcid: 5890818
Mendoza-Rodriguez MG, Ayala-Sumuano JT, Garcia-Morales L, Zamudio-Meza H, Perez-Yepez EA, Meza I (2019) IL-1beta inflammatory cytokine-induced TP63 isoform NP63alpha signaling cascade contributes to cisplatin resistance in human breast cancer cells. Int J Mol Sci. https://doi.org/10.3390/ijms20020270
doi: 10.3390/ijms20020270
pubmed: 30641908
pmcid: 6358904
Diaz-Maroto NG, Garcia-Vicien G, Polcaro G, Banuls M, Albert N, Villanueva A, Mollevi DG (2021) The blockade of tumoral il1beta-mediated signaling in normal colonic fibroblasts sensitizes tumor cells to chemotherapy and prevents inflammatory CAF activation. Int J Mol Sci. https://doi.org/10.3390/ijms22094960
doi: 10.3390/ijms22094960
pubmed: 34066976
pmcid: 8125420
Mitsunaga S, Ikeda M, Shimizu S et al (2013) Serum levels of IL-6 and IL-1beta can predict the efficacy of gemcitabine in patients with advanced pancreatic cancer. Br J Cancer 108:2063–2069. https://doi.org/10.1038/bjc.2013.174
doi: 10.1038/bjc.2013.174
pubmed: 23591198
pmcid: 3670479
Jaras M, Johnels P, Hansen N et al (2010) Isolation and killing of candidate chronic myeloid leukemia stem cells by antibody targeting of IL-1 receptor accessory protein. Proc Natl Acad Sci U S A 107:16280–16285. https://doi.org/10.1073/pnas.1004408107
doi: 10.1073/pnas.1004408107
pubmed: 20805474
pmcid: 2941341
Askmyr M, Agerstam H, Hansen N et al (2013) Selective killing of candidate AML stem cells by antibody targeting of IL1RAP. Blood 121:3709–3713. https://doi.org/10.1182/blood-2012-09-458935
doi: 10.1182/blood-2012-09-458935
pubmed: 23479569
Shastri A, Will B, Steidl U, Verma A (2017) Stem and progenitor cell alterations in myelodysplastic syndromes. Blood 129:1586–1594. https://doi.org/10.1182/blood-2016-10-696062
doi: 10.1182/blood-2016-10-696062
pubmed: 28159737
pmcid: 5364336
Fioretos T, Jaras M (2012) Method of treating a solid tumor with IL1RAP antibodies. US Patent No. 10,005,841
Robbrecht D, Jungels C, Sorensen MM et al (2021) First-in-human phase 1 dose-escalation study of CAN04, a first-in-class interleukin-1 receptor accessory protein (IL1RAP) antibody in patients with solid tumours. Br J Cancer. https://doi.org/10.1038/s41416-021-01657-7
doi: 10.1038/s41416-021-01657-7
pubmed: 34903842
pmcid: 8980035
Fields JK, Kihn K, Birkedal GS et al (2021) Molecular basis of selective cytokine signaling inhibition by antibodies targeting a shared receptor. Front Immunol 12:779100. https://doi.org/10.3389/fimmu.2021.779100
doi: 10.3389/fimmu.2021.779100
pubmed: 35003094
pmcid: 8740070
Gottschlich A, Endres S, Kobold S (2021) Therapeutic strategies for targeting IL-1 in cancer. Cancers (Basel). https://doi.org/10.3390/cancers13030477
doi: 10.3390/cancers13030477
pubmed: 33530653
pmcid: 7611996
Paulus A, Cicenas S, Zvirbule Z, Paz-Ares L, Awada A, Garcia-Ribas I, Losic N, Zemaitis M (2022) Phase 1/2a trial of nadunolimab, a first-in-class fully humanized monoclonal antibody against IL1RAP, in combination with cisplatin and gemcitabine (CG) in patients with non-small cell lung cancer (NSCLC). J Clin Oncol. 40: 9020. doi: https://doi.org/10.1200/JCO.2022.40.16_suppl.9020
Van Cutsem E, Løvendahl Eefsen R, Ochsenreither S et al. (2022) Phase 1/2a trial of nadunolimab, a first-in-class fully humanized monoclonal antibody against IL1RAP, in combination with gemcitabine and nab-paclitaxel (GN) in patients with pancreatic adenocarcinoma (PDAC). J Clin Oncol. 40: 4141. doi: https://doi.org/10.1200/JCO.2022.40.16_suppl.4141
Yang M, Shan B, Li Q et al (2013) Overcoming erlotinib resistance with tailored treatment regimen in patient-derived xenografts from naive Asian NSCLC patients. Int J Cancer 132:E74-84. https://doi.org/10.1002/ijc.27813
doi: 10.1002/ijc.27813
pubmed: 22948846
Porter AG, Janicke RU (1999) Emerging roles of caspase-3 in apoptosis. Cell Death Differ 6:99–104. https://doi.org/10.1038/sj.cdd.4400476
doi: 10.1038/sj.cdd.4400476
pubmed: 10200555
Huo KG, D’Arcangelo E, Tsao MS (2020) Patient-derived cell line, xenograft and organoid models in lung cancer therapy. Transl Lung Cancer Res 9:2214–2232. https://doi.org/10.21037/tlcr-20-154
doi: 10.21037/tlcr-20-154
pubmed: 33209645
pmcid: 7653147
Lieberthal W, Triaca V, Levine J (1996) Mechanisms of death induced by cisplatin in proximal tubular epithelial cells: apoptosis vs. necrosis. Am J Physiol 270:F700–F708. https://doi.org/10.1152/ajprenal.1996.270.4.F700
doi: 10.1152/ajprenal.1996.270.4.F700
pubmed: 8967349
Cohen I, Rider P, Carmi Y et al (2010) Differential release of chromatin-bound IL-1alpha discriminates between necrotic and apoptotic cell death by the ability to induce sterile inflammation. Proc Natl Acad Sci U S A 107:2574–2579. https://doi.org/10.1073/pnas.0915018107
doi: 10.1073/pnas.0915018107
pubmed: 20133797
pmcid: 2823886
Kudo-Saito C, Miyamoto T, Imazeki H, Shoji H, Aoki K, Boku N (2020) IL33 is a key driver of treatment resistance of cancer. Cancer Res 80:1981–1990. https://doi.org/10.1158/0008-5472.CAN-19-2235
doi: 10.1158/0008-5472.CAN-19-2235
pubmed: 32156776