2. Academic Validation
  3. Tumor-Derived Lysophosphatidic Acid Blunts Protective Type I Interferon Responses in Ovarian Cancer

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

  • Cancer Discov. 2022 Aug 5;12(8):1904-1921. doi: 10.1158/2159-8290.CD-21-1181.
Chang-Suk Chae 1,  Tito A Sandoval 1,  Sung-Min Hwang 1,  Eun Sil Park 2,  Paolo Giovanelli 3 4,  Deepika Awasthi 1,  Camilla Salvagno 1,  Alexander Emmanuelli 1 3,  Chen Tan 1,  Vidyanath Chaudhary 5,  Julia Casado 6 7,  Andrew V Kossenkov 8,  Minkyung Song 9,  Franck J Barrat 3 5,  Kevin Holcomb 1,  E Alfonso Romero-Sandoval 10,  Dmitriy Zamarin 11,  David Pépin 12 13,  Alan D D'Andrea 13,  Anniina Färkkilä 6 7,  Juan R Cubillos-Ruiz 1 3 14
Affiliations

Affiliations

  • 1 Department of Obstetrics and Gynecology, Weill Cornell Medicine, New York, New York.
  • 2 Department of Ophthalmology, Columbia University, New York, New York.
  • 3 Immunology and Microbial Pathogenesis Program, Weill Cornell Graduate School of Medical Sciences, New York, New York.
  • 4 Immunology Program, Memorial Sloan Kettering Cancer Center, New York, New York.
  • 5 HSS Research Institute and David Z. Rosensweig Genomics Research Center, Hospital for Special Surgery, New York, New York.
  • 6 Research Program in Systems Oncology, University of Helsinki, Helsinki, Finland.
  • 7 Department of Obstetrics and Gynecology, Helsinki University Hospital, Helsinki, Finland.
  • 8 Center for Systems and Computational Biology, The Wistar Institute, Philadelphia, Pennsylvania.
  • 9 Department of Integrative Biotechnology, College of Biotechnology and Bioengineering, and Department of Biopharmaceutical Convergence, Sungkyunkwan University, Suwon, Gyeonggi-do, Korea.
  • 10 Department of Anesthesiology, Pain Mechanisms Laboratory, Wake Forest University School of Medicine, Winston-Salem, North Carolina.
  • 11 Department of Medicine, Gynecologic Medical Oncology Service, Memorial Sloan Kettering Cancer Center, New York, New York.
  • 12 Pediatric Surgical Research Laboratories, Massachusetts General Hospital, Boston, Massachusetts. Department of Surgery, Harvard Medical School, Boston, Massachusetts.
  • 13 Susan F. Smith Center for Women's Cancers, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts.
  • 14 Sandra and Edward Meyer Cancer Center, Weill Cornell Medicine, New York, New York.
PMID: 35552618 DOI: 10.1158/2159-8290.CD-21-1181
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. See related commentary by Conejo-Garcia and Curiel, p. 1841. This article is highlighted in the In This Issue feature, p. 1825.

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