An Oncogenic Alteration Creates a Microenvironment that Promotes Tumor Progression by Conferring a Metabolic Advantage to Regulatory T Cells.

Only a small percentage of patients afflicted with gastric cancer (GC) respond to immune checkpoint blockade (ICB). To study the mechanisms underlying this resistance, we examined the immune landscape of GC. A subset of these tumors was characterized by high frequencies of regulatory T (Treg) cells and low numbers of effector T cells. Genomic analyses revealed that these tumors bore mutations in RHOA that are known to drive tumor progression. RHOA mutations in cancer cells activated the PI3K-AKT-mTOR signaling pathway, increasing production of free fatty acids that are more effectively consumed by Treg cells than effector T cells. RHOA mutant tumors were resistant to PD-1 blockade but responded to combination of PD-1 blockade with inhibitors of the PI3K pathway or therapies targeting Treg cells. We propose that the metabolic advantage conferred by RHOA mutations enables Treg cell accumulation within GC tumors, generating an immunosuppressive TME that underlies resistance to ICB. • RHOA Y42-mutated GC harbors abundant Treg cell and low CD8+ T cell infiltration in TME • RHOA Y42 mutations reduce CXCL10 and CXCL11 production via activated PI3K-AKT pathways • PI3K pathways activated by RHOA Y42 mutations provide a metabolic advantage for Treg cells • A PI3K inhibitor overcomes resistance to PD-1 blockade in RHOA Y42-mutated tumors Kumagai et al. find that a subset of gastric cancer (GC) tumors are characterized by high frequencies of regulatory T (Treg) cells and low numbers of effector T cells; these tumors bear mutations in RHOA. RHOA mutations activated the PI3K-AKT-mTOR pathway, increasing production of free fatty acids that are more effectively consumed by Treg cells than effector T cells. [ABSTRACT FROM AUTHOR]