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.

Keywords: SHP-1; adoptive cell transfer; checkpoint inhibitors; protein tyrosine phosphatase inhibition; tumour immunotherapy.

Figure 1. SHP-1 mediated inhibition of TCR signalling

SHP-1 is constitutively associated with the inhibitory receptor LAIR-1, which, in turn, is constitutively phosphorylated by Lck [74], although SHP-1 may also be activated by other ITIM-containing inhibitory receptors. Activation of SHP-1 allows it to inhibit antigen-induced TCR signalling either through direct dephosphorylation of the TCRζ chain, or dephosphorylation of downstream adaptor proteins such as Lck and ZAP70. Activating phosphate groups are shown as stars.

Figure 2. Lowered activation thresholds, increased duration of interaction with antigen presenting cells (green) and increased expansion of SHP-1^−/− CD8 T-cells are beneficial in tumour therapy

(1a) Tumour antigens (grey) are low affinity and poorly immunogenic, and offer limited stimulation to naïve T-cells (purple). (1b) Low numbers of tumour specific effector T-cells (red) are insufficient to control tumour growth. (2a) SHP-1^−/− T-cells have lower activation thresholds, therefore can be stimulated by low-affinity antigens. (2b) In response to antigen stimulation SHP-1^−/− T-cells proliferate more than WT T-cells, leading to increased numbers of tumour specific effector T-cells, and predicted control of tumour growth.