Tumor-Derived Lysophosphatidic Acid Blunts Protective Type I Interferon Responses in Ovarian Cancer

Chang Suk Chae, Tito A. Sandoval, Sung Min Hwang, Eun Sil Park, Paolo Giovanelli, Deepika Awasthi, Camilla Salvagno, Alexander Emmanuelli, Chen Tan, Vidyanath Chaudhary, Julia Casado, Andrew V. Kossenkov, Minkyung Song, Franck J. Barrat, Kevin Holcomb, E. Alfonso Romero-Sandoval, Dmitriy Zamarin, David Pépin, Alan D. D’andrea, Anniina FärkkiläJuan R. Cubillos-Ruiz

Research output: Contribution to journalArticlepeer-review

27 Scopus citations

Abstract

Lysophosphatidic acid (LPA) is a bioactive lipid enriched in the tumor microenvironment of immunosuppressive malignancies such as ovarian cancer. Although LPA enhances the tumorigenic attributes of cancer cells, the immunomodulatory activity of this phospholipid messenger remains largely unexplored. Here, we report that LPA operates as a negative regulator of type I interferon (IFN) responses in ovarian cancer. Ablation of the LPA-generating enzyme autotaxin (ATX) in ovarian cancer cells reprogrammed the tumor immune microenvironment, extended host survival, and improved the effects of therapies that elicit protective responses driven by type I IFN. Mechanistically, LPA sensing by dendritic cells triggered PGE2 biosynthesis that suppressed type I IFN signaling via autocrine EP4 engagement. Moreover, we identified an LPA-controlled, immune-derived gene signature associated with poor responses to combined PARP inhibition and PD-1 blockade in patients with ovarian cancer. Controlling LPA production or sensing in tumors may therefore be useful to improve cancer immunotherapies that rely on robust induction of type I IFN. SIGNIFICANCE: This study uncovers that ATX–LPA is a central immunosuppressive pathway in the ovarian tumor microenvironment. Ablating this axis sensitizes ovarian cancer hosts to various immunotherapies by unleashing protective type I IFN responses. Understanding the immunoregulatory programs induced by LPA could lead to new biomarkers predicting resistance to immunotherapy in patients with cancer.

Original languageEnglish
Pages (from-to)1904-1921
Number of pages18
JournalCancer Discovery
Volume12
Issue number8
DOIs
StatePublished - 1 Aug 2022
Externally publishedYes

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