RAD21 drives tumor progression and confers anti-PD-1 resistance by reprogramming tumor-associated macrophages via...

Area of Science:

• Oncology
• Immunology
• Molecular Biology

Background:

• Immune checkpoint inhibitors (ICIs) show promise in cancer therapy but face resistance. Tumor microenvironment (TME) remodeling by cancer cells contributes to this resistance. The role of RAD21 in tumor immunity is not well understood.
• RAD21, a cohesin subunit, frequently shows copy number variation (CNV) in human cancers. Its specific function in modulating the tumor immune response requires further elucidation.

Purpose of the Study:

• To investigate the role of RAD21 in tumor immunity and resistance to anti-PD-1 therapy.
• To identify RAD21 as a potential therapeutic target for overcoming ICI resistance.

Main Methods:

• Analysis of RAD21 copy number variation and expression across human cancers.
• Investigating the mechanism of RAD21-mediated immune evasion, including macrophage polarization and CSF1 signaling.
• Assessing the therapeutic efficacy of RAD21 depletion combined with anti-PD-1 blockade in preclinical models.

Main Results:

• RAD21 is identified as a frequently amplified oncogene associated with increased tumor cell proliferation, metastasis, and poor patient survival.
• Elevated RAD21 expression drives M2 polarization of tumor-associated macrophages (TAMs) through CSF1 signaling, creating an immunosuppressive TME and conferring resistance to anti-PD-1 therapy.
• RAD21 depletion reversed the immunosuppressive phenotype and, when combined with anti-PD-1 blockade, led to maximal tumor regression.

Conclusions:

• RAD21 orchestrates immune evasion by activating CSF1 signaling and promoting TAM M2 polarization, contributing to anti-PD-1 therapy resistance.
• Targeting RAD21 presents a promising strategy to overcome resistance to immune checkpoint inhibitors like anti-PD-1 therapy.