title: SHP-1: the next checkpoint target for cancer immunotherapy?
abstract: The immense power of the immune system is harnessed in healthy individuals by a range of negative regulatory signals and checkpoints. Manipulating these checkpoints through inhibition has resulted in striking immune-mediated clearance of otherwise untreatable tumours and metastases; unfortunately, not all patients respond to treatment with the currently available inhibitors of cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and programmed cell death protein 1 (PD-1). Combinatorial studies using both anti-CTLA-4 and anti-PD-1 demonstrate synergistic effects of targeting multiple checkpoints, paving the way for other immune checkpoints to be targeted. Src homology 2 domain-containing protein tyrosine phosphatase 1 (SHP-1) is a widely expressed inhibitory protein tyrosine phosphatase (PTP). In T-cells, it is a negative regulator of antigen-dependent activation and proliferation. It is a cytosolic protein, and therefore not amenable to antibody-mediated therapies, but its role in activation and proliferation makes it an attractive target for genetic manipulation in adoptive transfer strategies, such as chimeric antigen receptor (CAR) T-cells. This review will discuss the potential value of SHP-1 inhibition in future tumour immunotherapy.
authors.affiliation: Systems Immunity University Research Institute and Division of Infection and Immunity, School of Medicine, Henry Wellcome Building, Cardiff University, Heath Park, Cardiff, CF14 4XN, U.K. Watsonha1@cf.ac.uk.
authors.forename: H Angharad
authors.initials: HA
authors.lastname: Watson
authors.affiliation: Systems Immunity University Research Institute and Division of Infection and Immunity, School of Medicine, Henry Wellcome Building, Cardiff University, Heath Park, Cardiff, CF14 4XN, U.K.
authors.forename: Sophie
authors.initials: S
authors.lastname: Wehenkel
authors.affiliation: Systems Immunity University Research Institute and Division of Infection and Immunity, School of Medicine, Henry Wellcome Building, Cardiff University, Heath Park, Cardiff, CF14 4XN, U.K.
authors.forename: James
authors.initials: J
authors.lastname: Matthews
authors.affiliation: Systems Immunity University Research Institute and Division of Infection and Immunity, School of Medicine, Henry Wellcome Building, Cardiff University, Heath Park, Cardiff, CF14 4XN, U.K.
authors.forename: Ann
authors.initials: A
authors.lastname: Ager
mesh_terms: D019264:Adoptive Transfer; D006801:Humans; D007167:Immunotherapy; D008962:Models, Theoretical; D009369:Neoplasms / Q000628:therapy*; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6 / Q000276:immunology*
chemical_list: D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6
keywords: SHP-1; adoptive cell transfer; checkpoint inhibitors; protein tyrosine phosphatase inhibition; tumour immunotherapy