SHP2 inhibition triggers anti-tumor immunity and synergizes with PD-1 blockade

Area of Science:

• Immunology
• Oncology
• Pharmacology

Background:

• Tyrosine phosphatase SHP2 plays a dual role in cancer, promoting tumor growth and suppressing T-cell responses.
• SHP2 inhibition is a potential strategy for cancer immunotherapy.
• The precise mechanism by which SHP099, an allosteric SHP2 inhibitor, impacts anti-tumor immunity in vivo is not fully understood.

Purpose of the Study:

• To investigate whether SHP099-mediated SHP2 inhibition enhances anti-tumor immunity and retards tumor growth in vivo.
• To explore the therapeutic potential of SHP099 as a monotherapy and in combination with anti-PD-1 therapy in colon cancer models.

Main Methods:

• Establishment of CT-26 colon cancer xenograft models in immunocompetent and immunodeficient mice.
• Administration of SHP099 and/or anti-PD-1 antibody.
• Flow cytometry analysis of T-cell populations (CD8+IFN-γ+).
• Quantitative PCR analysis of cytotoxic T-cell genes (Granzyme B, Perforin).
• Assessment of tumor growth and burden.

Main Results:

• SHP099 significantly reduced tumor burden in immunocompetent mice, but not in immunodeficient mice, indicating an immune-dependent effect.
• SHP099 treatment increased the proportion of CD8+IFN-γ+ T cells and upregulated cytotoxic T-cell genes, enhancing anti-tumor immunity.
• SHP2-deficient T-cells led to slower tumor growth due to improved anti-tumor responses.
• Combination therapy with SHP099 and anti-PD-1 antibody demonstrated superior tumor growth control compared to monotherapy.

Conclusions:

• SHP2 inhibition by SHP099 promotes anti-tumor immunity, leading to reduced tumor growth in vivo.
• SHP099 is a promising candidate for cancer immunotherapy, particularly in combination with immune checkpoint inhibitors like anti-PD-1.