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.

Shp1 function in myeloid cells

“…This is particularly apparent in motheaten (me) mice that have a spontaneous mutation in Ptpn6, resulting in loss of Shp1, and develop a broad array of inflammatory and autoimmune symptoms. Given the important regulatory function of Shp1 in immune cells, there is growing interest in targeting this phosphatase in autoimmune disease and cancer [1,2]. Indeed, compounds that could enhance Shp1 function may be useful for suppression of immune function [3].…”

Targeting SHP-1, 2 and SHIP Pathways: A Novel Strategy for Cancer Treatment?

“…Of particular interest, however, is that SHP-1 was found to be inhibitory to T regulatory cells (T regs ) [33] suggesting that inhibition of SHP-1 in T regs may lead to increased suppressor function. As a result, this effect might be attributed to increases in TCR-APC conjugate formation and dura- [18]. Among them, SSG (approved treatment for leishmaniasis) has been studied in phase I trials in patients with malignant melanoma; however, results were disappointing (see below for details).…”

“…It is a cytosolic protein and therefore not amenable to antibody-mediated therapies, but its role in activation and proliferation could make it an attractive target for genetic manipulation in adoptive transfer strategies, such as chimeric antigen receptor (CAR) T cells [18].…”

“…This strong validation of SHP-1, 2 and SHIP as oncology targets has generated considerable interest in the development of small molecule inhibitors as potential therapeutic agents for haematologic malignancies and solid tumours [12,[16][17][18]. Unfortunately, SHP-1, 2 and SHIP have proven to be an extremely difficult target for drug discovery, primarily due to the highly conserved and positively charged nature of its PTP active site [19], and PTP inhibitor development has sent many pharmaceutical companies to the graveyard in the last decade.…”

“…The majority of reported PTP inhibitors lack either appropriate selectivity or membrane permeability, limiting their capacity in modulating the activity of the intracellular PTPs [18]. In order to overcome these caveats, novel techniques have been employed to synthesise new inhibitors that specifically attenuate the PTP-dependent signaling inside the cell and, amongst them, some are already in clinical phase I development [11,16,19,20].…”