Bioengineer mesenchymal stem cell for treatment of glioma by IL-12 mediated microenvironment reprogramming and nCD17-SLAMF7 mediated phagocytosis regulation of macrophages

Abstract

High expression of cellular self-activated immunosuppressive molecules and extensive infiltration of suppressive immune cells in the tumor microenvironment are the main factors contributing to glioma’s resistance to immunotherapy. Nonetheless, technology to modify the expression of glioma cellular self-molecules through gene editing requires further development. This project advances cell therapy strategies to reverse the immunosuppressive microenvironment of glioma (TIME). Bone marrow-derived mesenchymal stem cells (MSCs) are engineered to express bioactive proteins and demonstrate tumor-homing characteristics upon activation by TGF-β. TheseMSCs are designed to secrete the anti-tumor immune cytokine IL-12 and the nCD47-SLAMF7 fusion protein, which regulates T-cell activity and macrophage phagocytosis. The engineered MSCs are then injected in situ into the glioma site, circumventing the blood-brain barrier to deliver high local concentrations of bioactive proteins. This approach aims to enhance the M1 polarization of infiltrating macrophages, stimulate macrophage-mediated tumor cell phagocytosis, activate antigen-presenting cells, and promote effector CD8⁺ T cell infiltration, effectively controlling glioma. Additionally, the engineered MSCs may serve as a universal treatment for other tumors that express TGF-β at high levels. This study proposes a novel treatment strategy for the clinical management of glioma patients.

Keywords

CD47-SLAMF7 / glioma / mesenchymal stem cells

References

[1] M. J. van den Bent, M. Geurts, P. J. French, M. Smits, D. Capper, J. E. C. Bromberg, S. M. Chang, Lancet 2023, 402, 1564.

[2] J. H. Sampson, M. D. Gunn, Nat. Rev. Cancer 2020, 20, 12.

[3] G. Morad, B. A. Helmink, P. Sharma, J. A. Wargo, Cell 2021, 184, 5309.

[4] D. F. Quail, J. A. Joyce, Cancer Cell 2017, 31, 326.

[5] L. He, H. Zhou, Z. Zeng, H. Yao, W. Jiang, H. Qu, J. Cell. Physiol. 2019, 234, 2217.

[6] X.-C. Ding, L.-L. Wang, X.-D. Zhang, J.-L. Xu, P.-F. Li, H. Liang, X.-B. Zhang, L. Xie, Z.-H. Zhou, J. Yang, R. R. Weichselbaum, J.-CM. Yu, M. Hu, J. Hematol. Oncol. 2021, 14, 92.

[7] L. Zhai, A. Bell, E. Ladomersky, K. L. Lauing, L. Bollu, J. A. Sosman, B. Zhang, J. D. Wu, S. D. Miller, J. J. Meeks, R. V. Lukas, E. Wyatt, L. Doglio, G. E. Schiltz, R. H. McCusker, D. A. Wainwright, Front. Immunol. 2020, 11, 1185.

[8] J. Qiu, Q. Li, K. A. Bell, X. Yao, Y. Du, E. Zhang, J. J. Yu, Y. Yu, Z. Shi, J. Jiang, Br. J. Pharmacol. 2019, 176, 1680.

[9] a)Y. Mi, N. Guo, J. Luan, J. Cheng, Z. Hu, P. Jiang, W. Jin, X. Gao, Front. Immunol. 2020, 11, 737; b)P. Kadiyala, S. V. Carney, J. C. Gauss, M. B Garcia-Fabiani, S. Haase, M. S. Alghamri, F. J. Núñez, Y. Liu, M. Yu, A. Taher, F. M. Nunez, D. Li, M. B. Edwards, C. G. Kleer, H. Appelman, Y. Sun, L. Zhao, J. J. Moon, A. Schwendeman, P. R. Lowenstein, M. G. Castro, J. Clin. Invest. 2021, 4, 131.

[10] A. Christofides, L. Strauss, A. Yeo, C. Cao, A. Charest, Nat. Immunol. 2022, 23, 1148.

[11] W. Zhang, Q. Huang, W. Xiao, Y. Zhao, J. Pi, H. Xu, H. Zhao, J. Xu, C. E. Evans, H. Jin, Front. Immunol. 2020, 11, 18.

[12] N. Jiang, B. Xie, W. Xiao, M. Fan, S. Xu, Y. Duan, Y. Hamsafar, A. C. Evans, J. Huang, W. Zhou, X. Lin, N. Ye, S. Wanggou, W. Chen, D. Jing, R. C. Fragoso, B. N. Dugger, P. F. Wilson, M. A. Coleman, S. Xia, X. Li, L. Q. Sun, Nat. Commun. 2022, 13, 1511.

[13] Z. Tang, M. C. Zhong, J. Qian, C. C. Galindo, Nat. Immunol. 2023, 24, 2032.

[14] Z. Jiang, H. Sun, J. Yu, J. Hematol. Oncol. 2021, 14, 180.

[15] Y. Lu, K. Huntoon, Nat. Nanotechnol. 2022, 17, 1332.

[16] a)Y. Zhao, X. Zhou, Immunotherapy 2020, 12, 653;b)Y. Chen, Z. Yu, X. Tan, H. Jiang, Z. Xu, Y. Fang, D. Han, W. Hong, W. Wei, J. Tu, Biomed. Pharmacother. 2021, 139, 111605;c)G. Dolton, C. Rius, A. Wall, B. Szomolay, V. Bianchi, S. A. E. Galloway, M. S. Hasan, T. Morin, M. E. Caillaud, H. L. Thomas, S. Theaker, L. R. Tan, A. Fuller, K. Topley, M. Legut, M. Attaf, J. R. Hopkins, E. Behiry, J. Zabkiewicz, C. Alvares, A. Lloyd, A. Rogers, P. Henley, C. Fegan, O. Ottmann, S. Man, M. D. Crowther, M. Donia, I. M. Svane, D. K. Cole, P. E. Brown, P. Rizkallah, A. K. Sewell, Cell 2023, 186, 3333;d)L. Ma, A. Hostetler, D. M. Morgan, L. Maiorino, I. Sulkaj, C. A. Whittaker, A. Neeser, I. S. Pires, P. Yousefpour, J. Gregory, K. Qureshi, J. Dye, W. Abraham, H. Suh, N. Li, J. C. Love, D. J. Irvine, Cell 2023, 186, 3148.

[17] D. M. O’Rourke, M. P. Nasrallah, Sci. Transl. Med. 2017, 9，399.

[18] a)M. F. Pittenger, D. E. Discher, B. M. Péault, D. G. Phinney, npj Regener. Med. 2019, 4, 22; b)A.Andrzejewska, S. Dabrowska, B. Lukomska, M. Janowski, Adv. Sci. 2021, 8, 2002944.

[19] D. Bhere, S. H. Choi, P. van de Donk, D. Hope, Nat. Commun. 2022, 13, 2810.

[20] Z. Weng, B. Zhang, C. Wu, F. Yu, B. Han, B. Li, L. Li, J. Hematol. Oncol. 2021, 14, 136.

[21] E. A. Kimbrel, R. Lanza, Nat. Rev. Drug Discovery 2020, 19, 463.

[22] C. Vicinanza, E. Lombardi, F. Da Ros, M. Marangon, C. Durante, M. Mazzucato, F. Agostini, World J. Stem Cells 2022, 14, 54.

[23] M. Li, L. Zeng, S. Liu, S. Dangelmajer, U. D. Kahlert, H. Huang, Y. Han, X. Chi, M. Zhu, T. Lei, J. Neuropathol. Exp. Neurol. 2019, 78, 315.

[24] M. Li, S. Sun, S. Dangelmajer, Q. Zhang, J. Wang, F. Hu, F. Dong, U. D. Kahlert, M. Zhu, T. Lei, Stem Cell Res. Ther. 2019, 10, 88.

[25] a)E. Gutierrez, M. Bigelow, C. LaCroix, J. Beech, P. Kirby, L. Markowitz, M. Shifrin, M. Naill, A. Braun, S. O’Neil, J. M. Cuillerot, A. Cheung, A. Grinberg, N. Wagtmann, Medicine 2023, 4, 326;200.b)Y. Agarwal, L. E. Milling, J. Y. H. Chang, Nat. Biomed. Eng. 2022, 6, 129.

[26] S. Chowdhury, S. Castro, C. Coker, T. E. Hinchliffe, N. Arpaia, Nat. Med. 2019, 25, 1057.

[27] J. Chen, M. C. Zhong, H. Guo, D. Davidson, S. Mishel, Y. Lu, I. Rhee, L. A. Pérez-Quintero, S. Zhang, M. E Cruz-Munoz, N. Wu, D. C. Vinh, M. Sinha, V. Calderon, C. A. Lowell, J. S. Danska, A. Veillette, Nature 2017, 544, 493.

[28] C. Huang, X. Wang, Y. Wang, Y. Feng, X. Wang, S. Chen, P. Yan, J. Liao, Q. Zhang, C. Mao, Y. Li, L. Wang, X. Wang, W. Yi, W. Cai, Nat. Cancer 2024, 5, 500.

[29] a)L. Ye, W. Lv, W. He, S. Li, Z. Min, L. Gong, Q. Zhang, C. Teng, S. Sun, L. Lv, Y. Guo, H. Xin, J. Controlled Release 2023, 359, 224;b)C. Chen, W. Jing, Sci. Transl. Med. 2022, 14, eabn1128.

[30] B. C. Lo, I. Kryczek, Sci. Transl. Med. 2024, 383, 62.

[31] X. Dai, L. Lu, S. Deng, J. Meng, C. Wan, J. Huang, Y. Sun, Y. Hu, B. Wu, G. Wu, J. F. Lovell, H. Jin, K. Yang, Theranostics 2020, 10, 9332.

[32] M. J. Goldman, B. Craft, Nat. Biotechnol. 2020, 38, 675.

[33] S. Hänzelmann, R. Castelo, J. Guinney, BMC Bioinf. 2013, 14, 7.

[34] P. Charoentong, F. Finotello, M. Angelova, C. Mayer, M. Efremova, D. Rieder, H. Hackl, Z. Trajanoski, Cell Rep. 2017, 18, 248.

[35] Y. T. Shih, M. C. Wang, H. H. Peng, T. F. Chen, L. Chen, J. Y. Chang, J. J. Chiu, Cell. Signalling 2012, 24, 779.

[36] L. Lu, S. Qi, Y. Chen, H. Luo, S. Huang, X. Yu, Q. Luo, Z. Zhang, Biomaterials 2020, 245, 119987.

RIGHTS & PERMISSIONS

2024 The Author(s). Exploration published by Henan University and John Wiley & Sons Australia, Ltd.