# Tumor-derived RAC1A159V mutation promotes an immunosuppressive microenvironment that represses response to immune checkpoint inhibitor

## TL;DR

A specific RAC1 mutation in tumors creates an environment that suppresses immune responses, making immunotherapy less effective.

## Contribution

The study reveals how the RAC1A159V mutation promotes immune evasion and suggests a treatment strategy combining mTOR inhibition with immunotherapy.

## Key findings

- RAC1A159V tumors grow faster and resist PD1 immunotherapy in immune-competent mice.
- The mutation increases mTOR signaling and reduces tumor-immune cell interactions, creating 'cold' tumors.
- mTORC1 inhibition with rapamycin restores PD1 treatment effectiveness in RAC1A159V tumors.

## Abstract

RAC1A159V is a hotspot mutation associated with poor prognosis in several cancers. By gene editing, we generated endogenous homozygous and heterozygous RAC1A159V mutations, which result in up-regulated RAC1 activity and mammalian target of rapamycin (mTOR) signaling. RAC1A159V tumors grow faster than RAC1WT tumors in immune-proficient mice and are resistant to anti–programmed death protein 1 (PD1). Flow cytometry and scRNA-seq analyses reveal that RAC1A159V cells form “cold” tumors with an immunosuppressive microenvironment and reduced tumor-immune cell interactions. Mechanistically, RAC1A159V up-regulates glycosphingolipid biosynthesis to activate mTORC1 signaling in tumor cells, which in turn increases glycolysis, impairs key chemokine production, and decreases IFNGR1 expression of the tumor cells. mTORC1 inhibition by rapamycin resensitizes the RAC1A159V tumors to anti-PD1 treatment by reversing effects of RAC1A159V mutation. These results demonstrate a mechanism of RAC1A159V-driven immune evasion and suggest an approach of combining the targeting of RAC1-mTOR signaling with immune checkpoint inhibitor for the treatment of a type of immune-cold tumors.

The tumor-derived RAC1A159V mutation fosters an immune-cold microenvironment, limiting response to checkpoint immunotherapy.