SHP2 Targets ITK Downstream of PD-1 to Inhibit T Cell Function

Area of Science:

• Immunology
• Molecular Biology
• Oncology

Background:

• Programmed cell death protein 1 (PD-1) is a crucial target in cancer immunotherapy, with PD-1 blocking antibodies approved for various cancers.
• SH2-containing protein tyrosine phosphatase 2 (SHP2) is the primary effector of PD-1 downstream signaling, making it an alternative therapeutic target.
• Previous attempts to target SHP2 with small molecule inhibitors have yielded unexpected results, indicating a complex role for SHP2 in T cells.

Purpose of the Study:

• To elucidate the complex role of SHP2 in T cell signaling downstream of PD-1.
• To identify specific molecular players involved in PD-1 inhibitory functions.

Main Methods:

• Interactome mapping of the adapter protein SAP, which is linked to SHP2 signaling.
• Genetic and pharmacological approaches to investigate SHP2 activity in T cells.
• Analysis of protein dephosphorylation events mediated by SHP2.

Main Results:

• SHP2 was found to specifically dephosphorylate Interleukin-2-inducible T-cell kinase (ITK) downstream of PD-1.
• This SHP2-mediated dephosphorylation of ITK is associated with PD-1's inhibitory functions in T cells.
• ITK acts as a SHP2-dependent mediator of PD-1 signaling.

Conclusions:

• ITK is identified as a unique and critical target within the PD-1 signaling pathway.
• Combining ITK inhibitors with PD-1 blockade presents a promising strategy to improve cancer immunotherapy outcomes beyond PD-1 monotherapy.