journal contribution
posted on 2023-04-04, 00:01 authored by 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 Färkkilä, Juan R. Cubillos-Ruiz Supplementary Figure from Tumor-Derived Lysophosphatidic Acid Blunts Protective Type I Interferon Responses in Ovarian Cancer
Funding
U.S. Department of Defense Ovarian Cancer Research Program
Stand Up To Cancer Innovative Research Grant
Stand Up To Cancer Phillip A. Sharp Innovation in Collaboration Award
NIH
National Research Foundation of Korea
National Cancer Center of Korea
History
ARTICLE 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.
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.See related commentary by Conejo-Garcia and Curiel, p. 1841.This article is highlighted in the In This Issue feature, p. 1825
