TY - JOUR
T1 - Tumor-Derived Lysophosphatidic Acid Blunts Protective Type I Interferon Responses in Ovarian Cancer
AU - Chae, Chang Suk
AU - Sandoval, Tito A.
AU - Hwang, Sung Min
AU - Park, Eun Sil
AU - Giovanelli, Paolo
AU - Awasthi, Deepika
AU - Salvagno, Camilla
AU - Emmanuelli, Alexander
AU - Tan, Chen
AU - Chaudhary, Vidyanath
AU - Casado, Julia
AU - Kossenkov, Andrew V.
AU - Song, Minkyung
AU - Barrat, Franck J.
AU - Holcomb, Kevin
AU - Romero-Sandoval, E. Alfonso
AU - Zamarin, Dmitriy
AU - Pépin, David
AU - D’andrea, Alan D.
AU - Färkkilä, Anniina
AU - Cubillos-Ruiz, Juan R.
N1 - Publisher Copyright:
© 2022 American Association for Cancer Research.
PY - 2022/8/1
Y1 - 2022/8/1
N2 - 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.
AB - 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.
UR - https://www.scopus.com/pages/publications/85135529231
U2 - 10.1158/2159-8290.CD-21-1181
DO - 10.1158/2159-8290.CD-21-1181
M3 - Article
C2 - 35552618
AN - SCOPUS:85135529231
SN - 2159-8274
VL - 12
SP - 1904
EP - 1921
JO - Cancer Discovery
JF - Cancer Discovery
IS - 8
ER -
