As an increasing variety of tumor immunotherapy approaches are successfully translated into the clinic, the search continues for ever more ingenious manipulations of the immune system in order to improve treatment outcomes. To date, immunotherapy approaches can be broadly classified into two types; antibody-mediated checkpoint inhibition, in which the patient’s immune system is manipulated on a global level to alleviate tumor-induced immune suppression, and adoptive cell transfer, where either the patient’s own tumor-specific T cells are extracted, expanded and/or modified ex-vivo before being reinfused, or chimeric antigen receptor T cells (CAR-T cells) are engineered for tumor specificit\and infused into patients. As SRC-homology domain-containing protein tyrosine phosphatase 1 (SHP-1) is a cytosolic protein, it cannot be inhibited by antibodies in the same way as anti-cytotoxic T-lymphocyte associated protein 4 (CTLA-4) and programmed death receptor-1 (PD-1), which are both cell surface proteins. Instead, approaches such as those using CRISPR/ Cas9 to abrogate gene expression must be used, making modifying SHP-1 a “bolt-on” modification such as those being used in so-called “armored CAR” T cells. Нerefore, therapies targeting SHP-1 span both checkpoint inhibition and adoptive cell transfer approaches.

Нe implications of this work for the clinical exploitation of SHP-1 inhibition for tumor immunotherapy are complex. On the one hand, the increased proliferative capacity of SHP-1null T cells makes it an attractive modification for cells destined for adoptive transfer, as cell number can be limiting in these strategies especially following genetic modification, which can result in a certain amount of cell death. On the other hand, the degree of improvement in tumor growth control over SHP-1 T cells, although significant, might have been expected to be more dramatic. However, our model utilised a viral TCR, while tumor-specific TCRs are notoriously low. SHP-1 is involved in the regulation of TCR activation thresholds; therefore in a real-world tumor specific T cell, SHP-1 inhibition may a greater improvement than observed in this model system. Improvement in the stability and duration of the immune synapse following SHP-1 ablation, together with a decrease in the TCR activation threshold could allow endogenous anti-tumor TCRs to be successfully utilised therapeutically. Currently, the problem of tumor-specific TCRs is addressed with strategies such as CAR T cells; however, bypassing the classic antigen presentation pathway has potential implications for other T cell pathways, such as homing. Where an appropriate target for a CAR T cell, such as CD19, is not available, and the tumor is not rich in the neoantigens that favour current checkpoint inhibition strategies, ablation of SHP-1 in adoptively-transferred tumor specific T cells could provide a solution for the treatment of cancers not currently amenable to immunotherapy.

Currently, several studies and trials are focusing on the use of pharmacological phosphatase inhibitors that target SHP-1 with varying levels of specific it\ as anti-cancer agents, however, the lung pathology observed in our study highlights some of the potential pitfalls of global SHP-1 inhibition. Our work indicates that the cells responsible for the pathology are not a homogenous population, and it is therefore possible that one population is responsible for the antitumor, and a separate population is causing the pathology. If the anti-tumor effects of the non-CD8 SHP-1null cells could be separated from the pathological effects, then SHP-1 abrogation in these cells could be a powerful, novel anti-cancer strategy.

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