Tumor-derived RAC1^A159V mutation promotes an immunosuppressive microenvironment that represses response to immune...

Area of Science:

• Oncology
• Cancer Biology
• Immunology

Background:

• The RAC1^A159V mutation is linked to poor cancer prognosis.
• Understanding RAC1^A159V's role in tumor growth and immune evasion is crucial.

Purpose of the Study:

• To investigate the functional consequences of endogenous RAC1^A159V mutations.
• To elucidate the mechanisms underlying RAC1^A159V-driven immune evasion.
• To explore therapeutic strategies for RAC1^A159V-associated cancers.

Main Methods:

• Gene editing to create RAC1^A159V mutations in mice.
• Flow cytometry and single-cell RNA sequencing (scRNA-seq) for immune profiling.
• Assessment of tumor growth and response to anti-PD1 therapy.
• Pharmacological inhibition of mTORC1 signaling.

Main Results:

• RAC1^A159V mutations up-regulate RAC1 and mTOR signaling, promoting faster tumor growth.
• RAC1^A159V tumors exhibit an immunosuppressive, "cold" microenvironment resistant to anti-PD1 therapy.
• The mutation increases glycosphingolipid biosynthesis, activating mTORC1, enhancing glycolysis, and reducing chemokine production and IFNGR1 expression.
• Rapamycin (mTORC1 inhibitor) resensitizes tumors to anti-PD1 by reversing these effects.

Conclusions:

• RAC1^A159V promotes immune evasion through mTORC1 activation, leading to a cold tumor phenotype.
• Targeting RAC1-mTOR signaling in combination with immune checkpoint inhibitors offers a potential therapeutic strategy for immune-cold tumors.