title: Transient exposure to proteins SOX2, Oct-4, and NANOG immortalizes exhausted tumor-infiltrating CTLs.
abstract: Adoptive cell transfer therapy (ACT) is one of the most promising immunotherapies against cancer, using tumor-infiltrating lymphocytes (TILs) expanded in vitro. Tumor-infiltrating cytotoxic T lymphocytes (TICTLs) play a prominent role in cancer control. TILs terminally differentiate in response to immunosuppressive environments within tumors, and thus are slow to expand and challenging to maintain both in vitro and in patients. To reverse this exhaustion, we utilize a nuclear protein delivery system that exposes TICTLs to the SOX2, Oct-4, and NANOG (SON) proteins. Unlike activated naïve CTLs (effector CTLs), TICTLs respond favorably to SON treatment, exhibiting steady proliferation and extended survivability independent of cytokine and antigen stimulation. Though TICTLs treated with SON (STICTLs) still express T cell receptors as well as other critical downstream components, they are unresponsive to antigen challenge, suggesting that SON treatment regresses TICTLs into a state similar to that of an early double negative T cell. Our findings indicate the TICTL response to SON proteins is unique when compared to effector CTLs, suggesting TICTLs may be sensitive to regulation by other lineage-specific transcription factors and opening a promising new avenue into cancer immunotherapy. To our knowledge, this is the first report on lineage reprogramming of TILs using protein stem cell transcription factors delivered directly to the nucleus.
authors.affiliation: Department of Animal and Avian Sciences, University of Maryland, College Park, 20742, MD, USA.
authors.forename: Anjuli
authors.initials: A
authors.lastname: Bhadurihauck
authors.affiliation: Department of Animal and Avian Sciences, University of Maryland, College Park, 20742, MD, USA.
authors.forename: Lei
authors.initials: L
authors.lastname: Li
authors.affiliation: Department of Biochemistry and Molecular Biology, Wayne State University, Detroit, 48201, USA.
authors.forename: Qianqian
authors.initials: Q
authors.lastname: Li
authors.affiliation: Department of Biochemistry and Molecular Biology, Wayne State University, Detroit, 48201, USA.
authors.forename: Jianjun
authors.initials: J
authors.lastname: Wang
authors.affiliation: Department of Animal and Avian Sciences, University of Maryland, College Park, 20742, MD, USA. Electronic address: xiao0028@umd.edu.
authors.forename: Zhengguo
authors.initials: Z
authors.lastname: Xiao
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D016219:Immunotherapy, Adoptive / Q000379:methods*; D016246:Lymphocytes, Tumor-Infiltrating / Q000276:immunology* / Q000637:transplantation*; D051379:Mice; D008822:Mice, Transgenic; D000071317:Nanog Homeobox Protein / Q000276:immunology*; D050814:Octamer Transcription Factor-3 / Q000276:immunology*; D055748:SOXB1 Transcription Factors / Q000276:immunology*; D013601:T-Lymphocytes / Q000276:immunology / Q000637:transplantation
chemical_list: D000071317:Nanog Homeobox Protein; C475540:Nanog protein, mouse; D050814:Octamer Transcription Factor-3; D055748:SOXB1 Transcription Factors; C527783:Sox2 protein, mouse
keywords: ACT; Nuclear delivery; SON; STICTLs; TICTLs; TILs