Tumor suppressor TET2 promotes cancer immunity and immunotherapy efficacy

Area of Science:

• Immunology
• Oncology
• Epigenetics

Background:

• Loss-of-function mutations in TET DNA dioxygenase genes are common in blood cancers but rare in solid tumors, where reduced activity is observed.
• The functional impact of diminished TET activity in solid tumors remains largely unknown, particularly concerning immune evasion and therapeutic response.

Purpose of the Study:

• To investigate the role of TET2 in regulating anti-tumor immunity and its impact on immunotherapy in solid tumors.
• To elucidate the molecular mechanisms by which TET2 influences immune cell infiltration and cancer progression.

Main Methods:

• Analysis of TET2 function in murine melanoma and colon tumor models.
• Investigating the interaction between interferon-gamma (IFNγ), JAK-STAT signaling, and TET2 in gene regulation.
• Assessing the effects of modulating TET2 activity using ascorbate (vitamin C) on tumor immunity and response to anti-PD-L1 therapy.

Main Results:

• TET2 mediates IFNγ-JAK-STAT signaling to control chemokine and PD-L1 expression, influencing lymphocyte infiltration and anti-tumor immunity.
• Reduced TET2 activity in solid tumors correlates with decreased TH1-type chemokines, fewer tumor-infiltrating lymphocytes (TILs), and cancer progression.
• Tet2 deletion in tumor cells promoted immune evasion and resistance to anti-PD-L1 therapy, while vitamin C administration enhanced anti-tumor immunity and immunotherapy efficacy.

Conclusions:

• A novel IFNγ-JAK-STAT-TET signaling pathway is identified, crucial for mediating tumor response to PD-1/PD-L1 blockade therapy.
• Disruption of this pathway is common in solid tumors, suggesting TET activity as a predictive biomarker for immunotherapy response.
• Stimulating TET activity presents a potential adjuvant immunotherapy strategy for solid tumors.