Abstract
Background
Cancer stem cells (CSCs) induce therapeutic resistance and may be an important barrier to cancer immunotherapy. Chimeric antigen receptor T (CAR-T) cell therapy has demonstrated remarkable efficacy in clinical settings. However, CAR-T cell therapy fails in a large proportion of patients, especially in those with solid tumors. It is unclear how CSCs mediate resistance to CAR-T cells, and whether CAR-T cells can more effectively eradicate CSCs.
Methods
In this study, the effect of CSCs on CAR-T cell therapy was determined using in vitro and in vivo assays. Subsequently, Interleukin-24 (IL-24) was expressed along with CAR in T cells. Further in vitro and in vivo tests were performed to determine the effects of IL-24 on CSCs and CAR-T cell therapy.
Results
IL-24 induced apoptosis in CSCs and contributed to T cell activation, differentiation, and proliferation. CAR.IL-24-T cells inhibited CSC enrichment and exhibited stronger antitumor activity in vitro and in vivo.
Conclusions
IL-24 helps eliminate CSCs and endows CAR-T cells with improved antitumor reactivity.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 24 print issues and online access
$259.00 per year
only $10.79 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
Data availability
The datasets used and/or analyzed during the current study are available from the corresponding author upon reasonable request.
References
Han J, Won M, Kim JH, Jung E, Min K, Jangili P, et al. Cancer stem cell-targeted bio-imaging and chemotherapeutic perspective. Chem Soc Rev. 2020;49:7856–78.
Clarke MF. Clinical and therapeutic implications of cancer stem cells. N. Engl J Med. 2019;381:e19.
Meacham CE, Morrison SJ. Tumour heterogeneity and cancer cell plasticity. Nature. 2013;501:328–37.
Prager BC, Xie Q, Bao S, Rich JN. Cancer stem cells: the architects of the tumor ecosystem. Cell Stem Cell. 2019;24:41–53.
Yang Y, Li X, Wang T, Guo Q, Xi T, Zheng L. Emerging agents that target signaling pathways in cancer stem cells. J Hematol Oncol. 2020;13:60.
Song M, Ping Y, Zhang K, Yang L, Li F, Zhang C, et al. Low-Dose IFNgamma induces tumor cell stemness in tumor microenvironment of non-small cell lung cancer. Cancer Res. 2019;79:3737–48.
Dana H, Chalbatani GM, Jalali SA, Mirzaei HR, Grupp SA, Suarez ER, et al. CAR-T cells: early successes in blood cancer and challenges in solid tumors. Acta Pharm Sin B. 2021;11:1129–47.
Wei J, Guo Y, Wang Y, Wu Z, Bo J, Zhang B, et al. Clinical development of CAR T cell therapy in China: 2020 update. Cell Mol Immunol. 2021;18:792–804.
June CH, Sadelain M. Chimeric antigen receptor therapy. N. Engl J Med. 2018;379:64–73.
Tian Y, Li Y, Shao Y, Zhang Y. Gene modification strategies for next-generation CAR T cells against solid cancers. J Hematol Oncol. 2020;13:54.
Tian Y, Wen C, Zhang Z, Liu Y, Li F, Zhao Q, et al. CXCL9-modified CAR T cells improve immune cell infiltration and antitumor efficacy. Cancer Immunol Immunother. 2022;71:2663–75.
Adachi K, Kano Y, Nagai T, Okuyama N, Sakoda Y, Tamada K. IL-7 and CCL19 expression in CAR-T cells improves immune cell infiltration and CAR-T cell survival in the tumor. Nat Biotechnol. 2018;36:346–51.
Li G, Guo J, Zheng Y, Ding W, Han Z, Qin L, et al. CXCR5 guides migration and tumor eradication of anti-EGFR chimeric antigen receptor T cells. Mol Ther Oncolytics. 2021;22:507–17.
Mei Z, Zhang K, Lam AK, Huang J, Qiu F, Qiao B, et al. MUC1 as a target for CAR-T therapy in head and neck squamous cell carinoma. Cancer Med. 2020;9:640–52.
Fultang L, Booth S, Yogev O, Martins B, Tubb V, Panetti S, et al. Metabolic engineering against the arginine microenvironment enhances CAR-T cell proliferation and therapeutic activity. Blood. 2020;136:1155–60.
Fu Y, Zou T, Shen X, Nelson PJ, Li J, Wu C, et al. Lipid metabolism in cancer progression and therapeutic strategies. MedComm. 2020;2:27–59.
Emdad L, Bhoopathi P, Talukdar S, Pradhan AK, Sarkar D, Wang XY, et al. Recent insights into apoptosis and toxic autophagy: the roles of MDA-7/IL-24, a multidimensional anti-cancer therapeutic. Semin Cancer Biol. 2020;66:140–54.
Casciello F, Kelly GM, Ramarao-Milne P, Kamal N, Stewart TA, Mukhopadhyay P, et al. Combined inhibition of G9a and EZH2 suppresses tumor growth via synergistic induction of IL24-mediated apoptosis. Cancer Res. 2022;82:1208–21.
Pradhan AK, Talukdar S, Bhoopathi P, Shen XN, Emdad L, Das SK, et al. mda-7/IL-24 mediates cancer cell-specific death via regulation of miR-221 and the Beclin-1 axis. Cancer Res. 2017;77:949–59.
Bhoopathi P, Lee N, Pradhan AK, Shen XN, Das SK, Sarkar D, et al. mda-7/IL-24 induces cell death in neuroblastoma through a novel mechanism involving AIF and ATM. Cancer Res. 2016;76:3572–82.
Dash R, Bhoopathi P, Das SK, Sarkar S, Emdad L, Dasgupta S, et al. Novel mechanism of MDA-7/IL-24 cancer-specific apoptosis through SARI induction. Cancer Res. 2014;74:563–74.
Panneerselvam J, Srivastava A, Mehta M, Chen A, Zhao YD, Munshi A, et al. IL-24 inhibits lung cancer growth by suppressing GLI1 and inducing DNA damage. Cancers. 2019;11:1879.
McKenzie T, Liu Y, Fanale M, Swisher SG, Chada S, Hunt KK. Combination therapy of Ad-mda7 and trastuzumab increases cell death in Her-2/neu-overexpressing breast cancer cells. Surgery. 2004;136:437–42.
Yacoub A, Hamed HA, Allegood J, Mitchell C, Spiegel S, Lesniak MS, et al. PERK-dependent regulation of ceramide synthase 6 and thioredoxin play a key role in mda-7/IL-24-induced killing of primary human glioblastoma multiforme cells. Cancer Res. 2010;70:1120–9.
Bhutia SK, Das SK, Azab B, Menezes ME, Dent P, Wang XY, et al. Targeting breast cancer-initiating/stem cells with melanoma differentiation-associated gene-7/interleukin-24. Int J Cancer. 2013;133:2726–36.
Cheng JZ, Yu D, Zhang H, Jin CS, Liu Y, Zhao X, et al. Inhibitive effect of IL-24 gene on CD133+ laryngeal cancer cells. Asian Pac J Trop Med. 2014;7:867–72.
Zhang Y, Liu Y, Xu Y. Interleukin-24 regulates T cell activity in patients with colorectal adenocarcinoma. Front Oncol. 2019;9:1401.
Wu Z, Liu W, Wang Z, Zeng B, Peng G, Niu H, et al. Mesenchymal stem cells derived from iPSCs expressing interleukin-24 inhibit the growth of melanoma in the tumor-bearing mouse model. Cancer Cell Int. 2020;20:33.
Rao LZ, Wang Y, Zhang L, Wu G, Zhang L, Wang FX, et al. IL-24 deficiency protects mice against bleomycin-induced pulmonary fibrosis by repressing IL-4-induced M2 program in macrophages. Cell Death Differ. 2021;28:1270–83.
Cunningham CC, Chada S, Merritt JA, Tong A, Senzer N, Zhang Y, et al. Clinical and local biological effects of an intratumoral injection of mda-7 (IL24; INGN 241) in patients with advanced carcinoma: a phase I study. Mol Ther. 2005;11:149–59.
Tong AW, Nemunaitis J, Su D, Zhang Y, Cunningham C, Senzer N, et al. Intratumoral injection of INGN 241, a nonreplicating adenovector expressing the melanoma-differentiation associated gene-7 (mda-7/IL24): biologic outcome in advanced cancer patients. Mol Ther. 2005;11:160–72.
Shi X, Zhang D, Li F, Zhang Z, Wang S, Xuan Y, et al. Targeting glycosylation of PD-1 to enhance CAR-T cell cytotoxicity. J Hematol Oncol. 2019;12:127.
Xuan Y, Sheng Y, Zhang D, Zhang K, Zhang Z, Ping Y, et al. Targeting CD276 by CAR-T cells induces regression of esophagus squamous cell carcinoma in xenograft mouse models. Transl Oncol. 2021;14:101138.
Gao Q, Wang S, Li F, Lian J, Cheng S, Yue D, et al. High mobility group protein B1 decreases surface localization of PD-1 to augment T-cell activation. Cancer Immunol Res. 2022;10:844–55.
Zhang K, Zhang L, Mi Y, Tang Y, Ren F, Liu B, et al. A ceRNA network and a potential regulatory axis in gastric cancer with different degrees of immune cell infiltration. Cancer Sci. 2020;111:4041–50.
Cheng S, Li F, Qin H, Ping Y, Zhao Q, Gao Q, et al. Long Noncoding RNA lncNDEPD1 regulates PD-1 expression via miR-3619-5p in CD8(+) T cells. J Immunol. 2022;208:1483–92.
Zhang Y, He L, Sadagopan A, Ma T, Dotti G, Wang Y, et al. Targeting radiation-resistant prostate cancer stem cells by B7-H3 CAR T cells. Mol Cancer Ther. 2021;20:577–88.
Seyfrid M, Maich WT, Shaikh VM, Tatari N, Upreti D, Piyasena D, et al. CD70 as an actionable immunotherapeutic target in recurrent glioblastoma and its microenvironment. J Immunother Cancer. 2022;10:e003289.
Miao Y, Yang H, Levorse J, Yuan S, Polak L, Sribour M, et al. Adaptive immune resistance emerges from tumor-initiating stem cells. Cell. 2019;177:1172–86.
Nusse R, Clevers H. Wnt/beta-Catenin signaling, disease, and emerging therapeutic modalities. Cell. 2017;169:985–99.
Hu C, Qian L, Miao Y, Huang Q, Miao P, Wang P, et al. Antigen-presenting effects of effector memory Vgamma9Vdelta2 T cells in rheumatoid arthritis. Cell Mol Immunol. 2012;9:245–54.
Li F, Zhang Z, Xuan Y, Zhang D, Liu J, Li A, et al. PD-1 abrogates the prolonged persistence of CD8(+) CAR-T cells with 4-1BB co-stimulation. Signal Transduct Target Ther. 2020;5:164.
Larson RC, Kann MC, Bailey SR, Haradhvala NJ, Llopis PM, Bouffard AA, et al. CAR T cell killing requires the IFNgammaR pathway in solid but not liquid tumours. Nature. 2022;604:563–70.
Hong M, Clubb JD, Chen YY. Engineering CAR-T cells for next-generation cancer therapy. Cancer Cell. 2020;38:473–88.
Fuca G, Reppel L, Landoni E, Savoldo B, Dotti G. Enhancing chimeric antigen receptor t cell efficacy in solid tumors. Clin Cancer Res. 2020;26:2444–51.
Zhu S, Zhang T, Zheng L, Liu H, Song W, Liu D, et al. Combination strategies to maximize the benefits of cancer immunotherapy. J Hematol Oncol. 2021;14:156.
Fan S, Gao H, Ji W, Zhu F, Sun L, Liu Y, et al. Umbilical cord-derived mesenchymal stromal/stem cells expressing IL-24 induce apoptosis in gliomas. J Cell Physiol. 2020;235:1769–79.
Alizadeh D, Wong RA, Yang X, Wang D, Pecoraro JR, Kuo CF, et al. IL15 enhances CAR-T cell antitumor activity by reducing mTORC1 activity and preserving their stem cell memory phenotype. Cancer Immunol Res. 2019;7:759–72.
Acknowledgements
The authors thank the patients and their families for their consent and participation in this clinical experiment.
Funding
This work was supported by grants from Ministry of Science and Technology (2022YFE0141000), National Natural Science Foundation of China (82272873, U2004115), Department of Science and Technology of Henan Province (221100310100, Z20221343036, SBGJ202101010, 201300310400), Health Commission of Henan Province (YXKC2021037), and First Affiliated Hospital of Zhengzhou University (QNCXTD2023010).
Author information
Authors and Affiliations
Contributions
FL, YZ and KZ designed this work and analyzed the data; KZ, WHH and CLW assisted with or performed experiments and analyses; LZ and LXZ assisted in providing tumor samples; KZ, FL and YZ wrote the manuscript; KZ and FL assisted in revising the manuscript.
Corresponding author
Ethics declarations
Competing interests
The authors declare that they have no competing or other interests that may be perceived to influence the results and/or discussion reported in this paper.
Ethics approval and consent to participate
The research protocol was reviewed and approved by the Ethics Committee of the First Affiliated Hospital of Zhengzhou University (2019-KY-258), and informed consent was obtained from all participants included in the study, in agreement with the institutional guidelines.
Consent for publication
The results/data/figures in this manuscript have not been published elsewhere, nor are they under consideration by another publisher.
Additional information
Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Rights and permissions
Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.
About this article
Cite this article
Zhang, K., Hu, W., Li, F. et al. IL-24 improves efficacy of CAR-T cell therapy by targeting stemness of tumor cells. Br J Cancer 130, 1337–1347 (2024). https://doi.org/10.1038/s41416-024-02601-1
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/s41416-024-02601-1