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.

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Déclaration de conflit d'intérêts

Declaration of interests Y.T. has received honoraria from Bristol-Myers Squibb, Ono Pharmaceutical, Chugai Pharmaceutical, Boehringer Ingelheim GmbH, MSD, and AstraZeneca and has received research funding from KOTAI biotechnologies outside of this work. T. Kuwata. has received research funding from Ono Pharmaceutical and has received honoraria from Chugai Pharmaceutical outside of this work. H.M. has served as a member of the scientific advisory board for Chugai Pharmaceutical and has received research funding from Ono Pharmaceutical outside of this work. K.S. has served as a member of the scientific advisory board for Ono Pharmaceutical, Eli Lilly, Bristol-Myers Squibb, Astellas Pharmaceutical, Takeda Pharmaceutical, and Pfizer; has received research funding from Ono Pharmaceutical, Eli Lilly, Sumitomo Dainippon Pharmaceutical, Daiichi-Sankyo, Taiho Pharmaceutical, Chugai Pharmaceutical, and MSD; and has received honoraria from Novartis Pharma, AbbVie GK, and Yakult Pharmaceutical Industry outside of this work. H.N. received research funding from Ono Pharmaceutical for this work, honoraria and research funding from Chugai Pharmaceutical and Bristol-Myers Squibb, honoraria from Ono Pharmaceutical and MSD, and research funding from Taiho Pharmaceutical, Daiichi-Sankyo, Kyowa Kirin, Zenyaku Kogyo, Oncolys BioPharma, Debiopharma, Asahi-Kasei, Astellas Pharmaceutical, Sumitomo Dainippon Pharmaceutical, Sysmex, and BD Japan outside this study. All the other authors declare that they have no competing financial interests.