Dual immunosuppression mechanism induced by PTP1B in colorectal cancer: upregulation of PD-L1 by FOXO1/miR-34C/c-MYC axis and inhibition of the infiltration of CD8(+) T cell by downregulating of CXCL11.

backgroundImmunotherapy is the latest revolution in cancer therapy. However, the majority of colorectal cancer (CRC) patients exhibit intrinsic immune tolerance. Accumulating evidence suggests that PTP1B plays an important role in the development and progression of CRC. Yet, as a potential intracellular immune checkpoint, its function and underlying mechanisms in immune regulation within CRC remain poorly understood.

methodsBioinformatics analysis of PTP1B was performed using data from TCGA and the Human Protein Atlas (HPA), followed by validation with fresh human CRC tissue samples. We generated stable PTP1B-knockdown and overexpressing CRC cell lines for subsequent functional investigations. These included clone formation, scratch wound healing, and Transwell assays to assess the impact of PTP1B on the malignant phenotype of CRC cells. To elucidate the molecular mechanisms by which PTP1B regulates PD-L1 and CXCL11 expression, we employed Western blotting, quantitative PCR, chromatin immunoprecipitation (ChIP), and confocal laser scanning microscopy. Furthermore, a co–culture model of CRC cells and CD8+ T cells was established, and Transwell and flow cytometry assays were conducted to determine how differential PTP1B expression in tumor cells influences CD8+ T cell infiltration and anti–tumor efficacy. Finally, a mouse subcutaneous xenograft model was utilized to evaluate the therapeutic potential and safety of combining PTP1B inhibition with anti–PD–1 treatment for CRC.

resultsPTP1B is highly expressed in CRC tissues and correlates closely with advanced pathological stage and poorer survival in patients. Elevated PTP1B expression promotes the proliferation, migration, and invasion of CRC cells. Mechanistically, PTP1B upregulates PD–L1 expression in CRC cells via the FOXO1/miR–34C/c–MYC pathway, conferring inherent tolerance to CD8+ T cells. Additionally, PTP1B inhibits the release of the chemokine CXCL11, impairing chemotaxis and reducing CD8+ T cell infiltration. Both in vitro co–culture assays and in vivo animal experiments demonstrate that PTP1B knockdown enhances the sensitivity of CRC cells to CD8+ T cells. When combined with anti–PD–1 therapy, PTP1B depletion synergistically enhances anti-tumor responses, suppresses the growth of subcutaneous mouse tumor grafts, and exhibits no significant impact on vital organs–including the heart, liver, spleen, kidney and lung–indicating a favorable safety profile.

conclusionsPTP1B fosters an immunosuppressive microenvironment in CRC through a dual mechanism: activating the FOXO1/miR–34C/c–MYC/PD–L1 signaling axis and suppressing CXCL11 secretion. Our findings establish the potential for the development of PTP1B inhibitors in combination with PD-1 blockade as a novel immunotherapeutic strategy for CRC.