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An Oncogenic Alteration Creates a Microenvironment that Promotes Tumor Progression by Conferring a Metabolic

Shogo Kumagai1, Yosuke Togashi2, Chika Sakai2

  • 1Division of Cancer Immunology, Research Institute/Exploratory Oncology Research and Clinical Trial Center (EPOC), National Cancer Center, Tokyo/Chiba, Japan; Department of Immunology, Nagoya University Graduate School of Medicine, Nagoya, Japan.

Immunity
|July 9, 2020
PubMed

Insights

Gastric cancer (GC) with RHOA mutations resists immune checkpoint blockade (ICB) by accumulating regulatory T (Treg) cells. Targeting PI3K or Treg cells combined with PD-1 blockade may overcome this resistance.

Area of Science:

  • Oncology
  • Immunology
  • Cancer Genomics

Background:

  • Immune checkpoint blockade (ICB) efficacy is limited in gastric cancer (GC).
  • Tumor immune microenvironment (TME) characteristics influence response to cancer therapies.
  • Regulatory T (Treg) cells can promote an immunosuppressive TME.

Purpose of the Study:

  • To investigate the mechanisms of resistance to ICB in GC.
  • To identify genomic alterations associated with ICB resistance in GC.
  • To explore potential therapeutic strategies to overcome ICB resistance in GC.

Main Methods:

  • Analysis of the immune landscape and genomic alterations in GC tumors.
  • Characterization of T cell populations (Treg and effector T cells) within the TME.
  • Assessment of the PI3K-AKT-mTOR signaling pathway and its metabolic consequences.
  • Evaluation of response to PD-1 blockade alone and in combination with PI3K inhibitors or Treg-targeting therapies.

Main Results:

  • A subset of GC tumors exhibited high Treg cell infiltration and low effector T cell numbers.
  • RHOA mutations were identified in GC tumors, correlating with increased Treg cells.
  • RHOA mutations activated the PI3K-AKT-mTOR pathway, increasing free fatty acid production utilized by Treg cells.
  • RHOA mutant GC tumors were resistant to PD-1 blockade but sensitive to combination therapies.

Conclusions:

  • RHOA mutations confer ICB resistance in GC by promoting Treg cell accumulation through metabolic reprogramming.
  • Targeting the PI3K pathway or Treg cells in combination with PD-1 blockade represents a promising therapeutic approach for RHOA-mutant GC.
Keywords:
PI3K inhibitorRHOA mutationfatty acid metabolismgastric cancernon-inflamed tumorregulatory T cell

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