A small molecule inhibitor of PTP1B and PTPN2 enhances T cell anti-tumor immunity

Area of Science:

• Immunology
• Pharmacology
• Oncology

Background:

• Protein tyrosine phosphatases 1B (PTP1B) and N2 (PTPN2) are key regulators of T cell function.
• Inhibiting PTP1B and PTPN2 is a promising strategy to enhance anti-tumor immunity.
• Existing PTP1B/PTPN2 inhibitors are under investigation for solid tumor treatment.

Purpose of the Study:

• To evaluate the therapeutic potential of a novel small-molecule inhibitor, Compound-182, targeting PTP1B and PTPN2.
• To assess Compound-182's effects on T cell-mediated anti-tumor immunity and tumor growth in preclinical models.
• To determine if Compound-182 can overcome resistance to existing cancer immunotherapies.

Main Methods:

• Compound-182 was characterized as a potent and selective active site competitive inhibitor of PTP1B and PTPN2.
• The effects of Compound-182 on T cell recruitment, activation, and tumor growth were evaluated in mouse models.
• Tumor responses to Compound-182, alone and in combination with α-PD-1 therapy, were assessed in both immunogenic and cold tumors.

Main Results:

• Compound-182 demonstrated potent inhibition of PTP1B and PTPN2, enhancing T cell recruitment and activation.
• Treatment with Compound-182 repressed tumor growth in mice without significant immune-related toxicities.
• Compound-182 showed differential effects in immunogenic (T cell-mediated) versus cold (direct tumor/T cell effects) tumors.
• Compound-182 sensitized tumors resistant to α-PD-1 therapy, improving treatment efficacy.

Conclusions:

• Small molecule inhibitors targeting PTP1B and PTPN2, such as Compound-182, hold significant potential for enhancing anti-tumor immunity.
• Compound-182 represents a promising therapeutic candidate for various solid tumors, potentially improving responses to checkpoint inhibitors.
• Targeting PTP1B/PTPN2 offers a viable strategy to combat cancer by modulating the tumor microenvironment and T cell function.