Approximately 22 % of human colorectal cancers (CRC) are characterized by IGF2 overexpression, and the tumor-promoting role of IGF2 has been widely reported. Despite promising preclinical results, IGF2 signaling inhibition therapy has exhibited limited efficacy in treating unselected patients with CRC. Recent evidence suggests that IGF2-high CRC are more sensitive to IGF2 signaling blockade therapy in immune-deficient mice, suggesting that IGF2-high CRC can benefit from IGF2 signaling blockade therapy. However, T cells are absent in immunodeficient mice, and the effect of blocking IGF2 signaling on T cell-mediated antitumor immunity remains unknown. Herein, using an implanted mouse tumor model in immunocompetent hosts, we report that PQ401, an IGF2-IGF1R inhibitor, significantly inhibited the growth of IGF2-high CRC cells. PQ401 treatment increased the infiltration and function of tumor-infiltrating CD4+ and CD8+ T cells in a T cell-extrinsic manner. Our findings suggest that myeloid-derived suppressor cells (MDSCs) highly express the IGF2 receptor IGF1R. Moreover, PQ401 treatment inhibits the suppressive function and recruitment of MDSCs, thereby promoting the anti-tumor activity of T cells. These results provide a potential therapeutic regimen for patients with IGF2-high CRC.
Keywords: Colorectal cancer; IGF1R; IGF2; Myeloid-derived suppressor cells; Tumor microenvironment.
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