Cancer discovery · 2022
Tumor-Derived Lysophosphatidic Acid Blunts Protective Type I Interferon Responses in Ovarian Cancer.
СтатьяПоддержка исследования: вне правительства СШАПоддержка NIH: внешняя программаПоддержка правительства СШАНазвание и аннотация: Перевод пока не подготовлен
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Chae Chang-Suk, Sandoval Tito A, Hwang Sung-Min, Park Eun Sil, Giovanelli Paolo, Awasthi Deepika, Salvagno Camilla, Emmanuelli Alexander, Tan Chen, Chaudhary Vidyanath, Casado Julia, Kossenkov Andrew V, Song Minkyung, Barrat Franck J, Holcomb Kevin, Romero-Sandoval E Alfonso, Zamarin Dmitriy, Pépin David, D'Andrea Alan D, Färkkilä Anniina, Cubillos-Ruiz Juan R
Аннотация
UNLABELLED: 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. See related commentary by Conejo-Garcia and Curiel, p. 1841. This article is highlighted in the In This Issue feature, p. 1825.
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. See related commentary by Conejo-Garcia and Curiel, p. 1841. This article is highlighted in the In This Issue feature, p. 1825.