iPSC modification strategies to induce immune tolerance

Abstract

Human pluripotent stem cells (hPSCs) hold great promise in regenerative medicine. However, immune rejections remain one of the major obstacles to stem cell therapy. Though conventional immunosuppressants are available in clinics, the side effects prevent the wide application of hPSCs derivatives, compromising both survival rate and quality of life. In recent years, a myriad of strategies aimed at inducing immune tolerance specifically by engineering stem cells has been introduced to society. One strategy involves human leukocyte antigen (HLA) deletion through gene editing, affording allografts the capability to evade the host immune system. Another strategy involves immune cloak, which is the focus of this review, with emphasis on the overexpression of immune checkpoints and the blocking of immune cytotoxic pathways. Nevertheless, co-transplantation with mesenchymal stem cells (MSCs) and enhanced MSCs confers immune privilege to engraftments. This review summarizes recent studies on the intricacies of immune tolerance induction by engineering stem cells. In addition, we endeavor to deliberate upon the safety and limitations associated with this promising and potential therapeutic modality.

Keywords

hPSC / HLA / gene editing / immune checkpoint

References

[1] Takahashi K , Yamanaka S . Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell 2006; 126: 663- 76.

[2] Strnadel J , Carromeu C , Bardy C , et al. Survival of syngeneic and allogeneic iPSC-derived neural precursors after spinal grafting in minipigs. Sci Transl Med 2018; 10: eaam6651.

[3] Yamanaka S . Pluripotent stem cell-based cell therapy—promise and challenges. Cell Stem Cell 2020; 27: 523- 31.

[4] Braud VM , Allan DSJ , O'Callaghan CA , et al. HLA-E binds to natural killer cell receptors CD94/NKG2A, B and C. Nature 1998; 391: 795- 9.

[5] van den Elsen PJ , Gobin SJP , van Eggermond MCJA , et al. Regulation of MHC class I and II gene transcription: differences and similarities. Immunogenetics 1998; 48: 208- 21.

[6] Zakrzewski JL , van den Brink MRM , Hubbell JA . Overcoming immunological barriers in regenerative medicine. Nat Biotechnol 2014; 32: 786- 94.

[7] Zhao T , Zhang Z-N , Rong Z , et al. Immunogenicity of induced pluripotent stem cells. Nature 2011; 474: 212- 5.

[8] de Almeida PE , Meyer EH , Kooreman NG , et al. Transplanted terminally differentiated induced pluripotent stem cells are accepted by immune mechanisms similar to self-tolerance. Nat Commun 2014; 5: 3903.

[9] Bogomiakova ME , Sekretova EK , Anufrieva KS , et al. iPSC-derived cells lack immune tolerance to autologous NK-cells due to imbalance in ligands for activating and inhibitory NK-cell receptors. Stem Cell Res Ther 2023; 14: 77.

[10] Briceño J , Ciria R , de la Mata M . Donor-recipient matching: myths and realities. J Hepatol 2013; 58: 811- 20.

[11] Adams DH , Sanchez-Fueyo A , Samuel D . From immunosuppression to tolerance. J Hepatol 2015; 62: S170- 85.

[12] Taylor CJ , Bolton EM , Pocock S , et al. Banking on human embryonic stem cells: estimating the number of donor cell lines needed for HLA matching. Lancet 2005; 366: 2019- 25.

[13] Hu Z , Fang M , Xu F , et al. Is pig organ xenotransplantation era approaching? Life Med 2022; 1: 241- 3.

[14] Xu H , Wang B , Ono M , et al. Targeted disruption of HLA genes via CRISPR-Cas9 generates iPSCs with enhanced immune compatibility. Cell Stem Cell 2019; 24: 566- 78.e7.

[15] Gornalusse GG , Hirata RK , Funk SE , et al. HLA-E-expressing pluripotent stem cells escape allogeneic responses and lysis by NK cells. Nat Biotechnol 2017; 35: 765- 72.

[16] Parent AV , Faleo G , Chavez J , et al. Selective deletion of human leukocyte antigens protects stem cell-derived islets from immune rejection. Cell Reports 2021; 36: 109538.

[17] Rong Z , Wang M , Hu Z , et al. An effective approach to prevent immune rejection of human ESC-derived allografts. Cell Stem Cell 2014; 14: 121- 30.

[18] Deuse T , Hu X , Gravina A , et al. Hypoimmunogenic derivatives of induced pluripotent stem cells evade immune rejection in fully immunocompetent allogeneic recipients. Nat Biotechnol 2019; 37: 252- 8.

[19] Gravina A , Tediashvili G , Rajalingam R , et al. Protection of cell therapeutics from antibody-mediated killing by CD64 overexpression. Nat Biotechnol 2023; 41: 717- 27.

[20] Gravina A , Tediashvili G , Zheng Y , et al. Synthetic immune checkpoint engagers protect HLA-deficient iPSCs and derivatives from innate immune cell cytotoxicity. Cell Stem Cell 2023; 30: 1538- 48.e4.

[21] Sintov E , Nikolskiy I , Barrera V , et al. Whole-genome CRISPR screening identifies genetic manipulations to reduce immune rejection of stem cell-derived islets. Stem Cell Rep 2022; 17: 1976- 90.

[22] Khan MA , Alanazi F , Ahmed HA , et al. iPSC-derived MSC therapy induces immune tolerance and supports long-term graft survival in mouse orthotopic tracheal transplants. Stem Cell Res Ther 2019; 10: 290.

[23] Wang X , Wang K , Yu M , et al. Engineered immunomodulatory accessory cells improve experimental allogeneic islet transplantation without immunosuppression. Sci Adv 2022; 8: eabn0071.

[24] Burr ML , Sparbier CE , Chan KL , et al. An evolutionarily conserved function of polycomb silences the MHC class I antigen presentation pathway and enables immune evasion in cancer. Cancer Cell 2019; 36: 385- 401.e8.

[25] Ichise H , Nagano S , Maeda T , et al. NK cell alloreactivity against KIR-ligand-mismatched HLA-haploidentical tissue derived from HLA haplotype-homozygous iPSCs. Stem Cell Rep 2017; 9: 853- 67.

[26] Wang D , Quan Y , Yan Q , et al. Targeted disruption of the β2-microglobulin gene minimizes the immunogenicity of human embryonic stem cells. Stem Cells Transl Med 2015; 4: 1234- 45.

[27] Mattapally S , Pawlik KM , Fast VG , et al. Human leukocyte antigen class I and II knockout human induced pluripotent stem cell-derived cells: universal donor for cell therapy. J Am Heart Assoc 2018; 7: e010239.

[28] Song C , Wang L , Li Q , et al. Generation of individualized immunocompatible endothelial cells from HLA-I-matched human pluripotent stem cells. Stem Cell Res Ther 2022; 13: 48.

[29] Han X , Wang M , Duan S , et al. Generation of hypoimmunogenic human pluripotent stem cells. Proc Natl Acad Sci U S A 2019; 116: 10441- 6.

[30] González BJ , Creusot RJ , Sykes M , et al. How safe are universal pluripotent stem cells? Cell Stem Cell 2020; 26: 307- 8.

[31] Matheus F , Raveh T , Oro AE , et al. Is hypoimmunogenic stem cell therapy safe in times of pandemics? Stem Cell Rep 2022; 17: 711- 4.

[32] Lanza R , Russell DW , Nagy A . Engineering universal cells that evade immune detection. Nat Rev Immunol 2019; 19: 723- 33.

[33] Ye Q , Sung T , Yang J , et al. Generation of universal and hypoimmunogenic human pluripotent stem cells. Cell Prolif 2020; 53: e12946.

[34] Anfossi N , André P , Guia S , et al. Human NK cell education by inhibitory receptors for MHC class I. Immunity 2006; 25: 331- 42.

[35] Parham P . MHC class I molecules and kirs in human history, health and survival. Nat Rev Immunol 2005; 5: 201- 14.

[36] Crew MD , Cannon MJ , Phanavanh B , et al. An HLA-E single chain trimer inhibits human NK cell reactivity towards porcine cells. Mol Immunol 2005; 42: 1205- 14.

[37] Jo S , Das S , Williams A , et al. Endowing universal CAR T-cell with immune-evasive properties using TALEN-gene editing. Nat Commun 2022; 13: 3453.

[38] Cross-Najafi AA , Farag K , Isidan A , et al. Co-expression of HLA-E and HLA-G on genetically modified porcine endothelial cells attenuates human NK cell-mediated degranulation. Front Immunol 2023; 14: 1217809.

[39] Spierings E , Kim Y-H , Hendriks M , et al. Multicenter analyses demonstrate significant clinical effects of minor histocompatibility antigens on GvHD and GvL after HLA-matched related and unrelated hematopoietic stem cell transplantation. Biol Blood Marrow Transplant 2013; 19: 1244- 53.

[40] Francisco LM , Sage PT , Sharpe AH . The PD-1 pathway in tolerance and autoimmunity. Immunol Rev 2010; 236: 219- 42.

[41] Yoshihara E , O'Connor C , Gasser E , et al. Immune-evasive human islet-like organoids ameliorate diabetes. Nature 2020; 586: 606- 11.

[42] Deuse T , Hu X , Agbor-Enoh S , et al. The SIRPα-CD47 immune checkpoint in NK cells. J Exp Med 2021; 218: e20200839.

[43] Hu X , White K , Olroyd AG , et al. Hypoimmune induced pluripotent stem cells survive long term in fully immunocompetent, allogeneic rhesus macaques. Nat Biotechnol 2023; 42: 413- 23.

[44] Gerace D , Zhou Q , Kenty JH-R , et al. Engineering human stem cell-derived islets to evade immune rejection and promote localized immune tolerance. Cell Rep Med 2022; 4: 100879.

[45] Ward NC , Yu A , Moro A , et al. IL-2/CD25: a long-acting fusion protein that promotes immune tolerance by selectively targeting the IL-2 receptor on regulatory T cells. J Immunol 2018; 201: 2579- 92.

[46] Harding J , Vintersten-Nagy K , Yang H , et al. Immune-privileged tissues formed from immunologically cloaked mouse embryonic stem cells survive long term in allogeneic hosts. Nat Biomed Eng 2023; 8: 427- 42.

[47] Lenschow D , Zeng Y , Thistlethwaite JR et al. Long-term survival of xenogeneic pancreatic islet grafts induced by CTLA4lg. Science 1992; 257: 789- 92.

[48] Green DR , Ferguson TA . The role of Fas ligand in immune privilege. Nat Rev Mol Cell Biol 2001; 2: 917- 24.

[49] Bouillet P , O'Reilly LA . CD95, BIM and T cell homeostasis. Nat Rev Immunol 2009; 9: 514- 9.

[50] Yamada A , Arakaki R , Saito M , et al. Dual role of Fas/FasL-mediated signal in peripheral immune tolerance. Front Immunol 2017; 8: 403.

[51] Headen DM , Woodward KB , Coronel MM , et al. Local immunomod-ulation with fas ligand-engineered biomaterials achieves allogeneic islet graft acceptance. Nat Mater 2018; 17: 732- 9.

[52] Woodward KB , Zhao H , Shrestha P , et al. Pancreatic islets engineered with a FasL protein induce systemic tolerance at the induction phase that evolves into long-term graft-localized immune privilege. Am J Transplant 2020; 20: 1285- 95.

[53] Lei J , Coronel MM , Yolcu ES , et al. FasL microgels induce immune acceptance of islet allografts in nonhuman primates. Sci Adv 2022; 8: eabm9881.

[54] Wang S . The promise of cancer therapeutics targeting the TNF-related apoptosis-inducing ligand and TRAIL receptor pathway. Oncogene 2008; 27: 6207- 15.

[55] Wu GS . TRAIL as a target in anti-cancer therapy. Cancer Lett 2009; 285: 1- 5.

[56] McCluskey J , Rossjohn J , Purcell AW . TAP genes and immunity. Curr Opin Immunol 2004; 16: 651- 9.

[57] Deaglio S , Dwyer KM , Gao W , et al. Adenosine generation catalyzed by CD39 and CD73 expressed on regulatory T cells mediates immune suppression. J Exp Med 2007; 204: 1257- 65.

[58] Uccelli A , Moretta L , Pistoia V . Mesenchymal stem cells in health and disease. Nat Rev Immunol 2008; 8: 726- 36.

[59] Eskandari SK , Daccache A , Azzi JR . Chimeric antigen receptor treg therapy in transplantation. Trends Immunol 2024; 45: 48- 61.

[60] Luca G , Arato I , Sorci G , et al. Sertoli cells for cell transplantation: pre- clinical studies and future perspectives. Andrology 2018; 6: 385- 95.

[61] Selawry HP , Cameron DF . Sertoli cell-enriched fractions in successful islet cell transplantation. Cell Transplant 1992; 2: 123- 9.

[62] Ar'rajab A , Dawidson IJA , Harris RB , et al. Immune privilege of the testis for islet xenotransplantation (rat to mouse). Cell Transplant 1994; 3: 493- 8.

[63] Ar'Rajab A , Dawidson IJ , Harris RB , et al. Immune privilege of the testis for islet xenotransplantation (rat to mouse). Transplant Proc 1994; 26: 3446.

[64] Luca G , Mancuso F , Calvitti M , et al. Long-term stability, functional competence, and safety of microencapsulated specific pathogen-free neonatal porcine sertoli cells: a potential product for cell transplant therapy. Xenotransplantation 2015; 22: 273- 83.

[65] Levy O , Kuai R , Siren EMJ , et al. Shattering barriers toward clinically meaningful MSC therapies. Sci Adv 2020; 6: eaba6884.

[66] Yoshida S , Miyagawa S , Toyofuku T , et al. Syngeneic mesenchymal stem cells reduce immune rejection after induced pluripotent stem cell-derived allogeneic cardiomyocyte transplantation. Sci Rep 2020; 10: 4593.

[67] Murata K , Ikegawa M , Minatoya K , et al. Strategies for immune regulation in iPS cell-based cardiac regenerative medicine. Inflamm Regen 2020; 40: 36.

[68] Hu X , Yu SP , Fraser JL , et al. Transplantation of hypoxia-preconditioned mesenchymal stem cells improves infarcted heart function via enhanced survival of implanted cells and angiogenesis. J Thorac Cardiovasc Surg 2008; 135: 799- 808.

[69] Li L , Chen X , Wang WE , et al. How to improve the survival of transplanted mesenchymal stem cell in ischemic heart? Stem Cells Int 2016; 2016: 9682757.

[70] Sakaguchi S , Sakaguchi N , Asano M , et al. Immunologic self-tolerance maintained by activated T cells expressing IL-2 receptor alpha-chains (CD25). breakdown of a single mechanism of self-tolerance causes various autoimmune diseases. J Immunol 1995; 155: 1151- 64.

[71] Trzonkowski P , Bieniaszewska M , Juścińska J , et al. First-in-man clinical results of the treatment of patients with graft versus host disease with human ex vivo expanded CD4+CD25+CD127- T regulatory cells. Clin Immunol 2009; 133: 22- 6.

[72] MacDonald KG , Hoeppli RE , Huang Q , et al. Alloantigen-specific regulatory T cells generated with a chimeric antigen receptor. J Clin Invest 2016; 126: 1413- 24.

[73] Mackensen A , Müller F , Mougiakakos D , et al. Anti-CD19 CAR T cell therapy for refractory systemic lupus erythematosus. Nat Med 2022; 28: 2124- 32.

[74] Sachs DH , Kawai T , Sykes M . Induction of tolerance through mixed chimerism. Cold Spring Harb Perspect Med 2014; 4: a015529.

[75] George BM , Kao KS , Kwon H-S , et al. Antibody conditioning enables MHC-mismatched hematopoietic stem cell transplants and organ graft tolerance. Cell Stem Cell 2019; 25: 185- 92.e3.

[76] Geering B , Fussenegger M . Synthetic immunology: modulating the human immune system. Trends Biotechnol 2015; 33: 65- 79.

[77] Harding J , Vintersten-Nagy K , Nagy A . Universal stem cells: making the unsafe safe. Cell Stem Cell 2020; 27: 198- 9.

[78] Hayashi R , Ishikawa Y , Katayama T , et al. CD200 facilitates the isolation of corneal epithelial cells derived from human pluripotent stem cells. Sci Rep 2018; 8: 16550.

[79] Liang Q , Monetti C , Shutova MV , et al. Linking a cell-division gene and a suicide gene to define and improve cell therapy safety. Nature 2018; 563: 701- 4.

[80] Kojima K , Miyoshi H , Nagoshi N , et al. Selective ablation of tumorigenic cells following human induced pluripotent stem cell-derived neural stem/progenitor cell transplantation in spinal cord injury. Stem Cells Transl Med 2019; 8: 260- 70.

[81] Mascola L , Lieb L , Fannin SL , et al. Listeriosis: an uncommon opportunistic infection in patients with acquired immunodeficiency syndrome a report of five cases and a review of the literature. Am J Med 1988; 84: 162- 4.

[82] Doudna JA . The promise and challenge of therapeutic genome editing. Nature 2020; 578: 229- 36.

[83] Baum C , Kustikova O , Modlich U , et al. Mutagenesis and oncogenesis by chromosomal insertion of gene transfer vectors. Hum Gene Ther 2006; 17: 253- 63.

[84] Feng S , Zhang T , Ke W , et al. The long-term survival and functional maturation of human iNPC-derived neurons in the basal forebrain of cynomolgus monkeys. Life Med 2022; 1: 196- 206.

[85] Doss MX , Sachinidis A . Current challenges of iPSC-based disease modeling and therapeutic implications. Cells 2019; 8: 403.

[86] Hu X , Gattis C , Olroyd AG , et al. Human hypoimmune primary pancreatic islets avoid rejection and autoimmunity and alleviate diabetes in allogeneic humanized mice. Sci Transl Med 2023; 15: eadg5794.

[87] Zhu F , Nie G , Liu C . Engineered biomaterials in stem cell-based regenerative medicine. Life Med 2023; 2: lnad027.

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