title: Purity of transferred CD8(+) T cells is crucial for safety and efficacy of combinatorial tumor immunotherapy in the absence of SHP-1.
abstract: Adoptive transfer of tumor-specific cytotoxic T cells is a promising advance in cancer therapy. Similarly, checkpoint inhibition has shown striking clinical results in some patients. Here we combine adoptive cell transfer with ablation of the checkpoint protein Src homology 2-domain-containing phosphatase 1 (SHP-1, Ptpn6). Naturally occurring motheaten mice lack SHP-1 and do not survive weaning due to extensive immunopathology. To circumvent this limitation, we created a novel SHP-1(null) mouse that is viable up to 12 weeks of age by knocking out IL1r1. Using this model, we demonstrate that the absence of SHP-1 augments the ability of adoptively transferred CD8(+) T cells to control tumor growth. This therapeutic effect was only observed in situations where T-cell numbers were limited, analogous to clinical settings. However, adoptive transfer of non-CD8(+) SHP-1(null) hematopoietic cells resulted in lethal motheaten-like pathology, indicating that systemic inhibition of SHP-1 could have serious adverse effects. Despite this caveat, our findings support the development of SHP-1 inhibition strategies in human T cells to complement adoptive transfer therapies in the clinic.
authors.affiliation: Division of Infection and Immunity, School of Medicine and Systems Immunity University Research Institute, Cardiff University, Cardiff, UK.
authors.forename: H Angharad
authors.initials: HA
authors.lastname: Watson
authors.affiliation: Division of Infection and Immunity, School of Medicine and Systems Immunity University Research Institute, Cardiff University, Cardiff, UK.
authors.forename: Garry
authors.initials: G
authors.lastname: Dolton
authors.affiliation: Division of Infection and Immunity, School of Medicine and Systems Immunity University Research Institute, Cardiff University, Cardiff, UK.
authors.forename: Julia
authors.initials: J
authors.lastname: Ohme
authors.affiliation: Division of Infection and Immunity, School of Medicine and Systems Immunity University Research Institute, Cardiff University, Cardiff, UK.
authors.forename: Kristin
authors.identifier: 0000-0002-9856-2938
authors.initials: K
authors.lastname: Ladell
authors.affiliation: Division of Infection and Immunity, School of Medicine and Systems Immunity University Research Institute, Cardiff University, Cardiff, UK.
authors.forename: Miriam
authors.initials: M
authors.lastname: Vigar
authors.affiliation: Division of Infection and Immunity, School of Medicine and Systems Immunity University Research Institute, Cardiff University, Cardiff, UK.
authors.forename: Sophie
authors.initials: S
authors.lastname: Wehenkel
authors.affiliation: Division of Infection and Immunity, School of Medicine and Systems Immunity University Research Institute, Cardiff University, Cardiff, UK.
authors.forename: James
authors.initials: J
authors.lastname: Hindley
authors.affiliation: Division of Infection and Immunity, School of Medicine and Systems Immunity University Research Institute, Cardiff University, Cardiff, UK.
authors.forename: Rebar N
authors.initials: RN
authors.lastname: Mohammed
authors.affiliation: Division of Infection and Immunity, School of Medicine and Systems Immunity University Research Institute, Cardiff University, Cardiff, UK.
authors.forename: Kelly
authors.initials: K
authors.lastname: Miners
authors.affiliation: Division of Infection and Immunity, School of Medicine and Systems Immunity University Research Institute, Cardiff University, Cardiff, UK.
authors.forename: Rhys A
authors.initials: RA
authors.lastname: Luckwell
authors.affiliation: Division of Infection and Immunity, School of Medicine and Systems Immunity University Research Institute, Cardiff University, Cardiff, UK.|Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA.
authors.forename: David A
authors.initials: DA
authors.lastname: Price
authors.affiliation: Division of Infection and Immunity, School of Medicine and Systems Immunity University Research Institute, Cardiff University, Cardiff, UK.
authors.forename: R James
authors.initials: RJ
authors.lastname: Matthews
authors.affiliation: Division of Infection and Immunity, School of Medicine and Systems Immunity University Research Institute, Cardiff University, Cardiff, UK.
authors.forename: Ann
authors.initials: A
authors.lastname: Ager
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D045744:Cell Line, Tumor; D005434:Flow Cytometry; D016219:Immunotherapy, Adoptive; D008546:Melanoma, Experimental / Q000276:immunology* / Q000628:therapy*; D008810:Mice, Inbred C57BL; D009362:Neoplasm Metastasis; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6 / Q000172:deficiency* / Q000378:metabolism; D053573:Receptors, Interleukin-1 Type I / Q000172:deficiency / Q000378:metabolism
chemical_list: C583355:IL1R1 protein, mouse; D053573:Receptors, Interleukin-1 Type I; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6