Tumor-Derived Lysophosphatidic Acid Blunts Protective Type I Interferon Responses in Ovarian Cancer-Reference-Cited by-同舟云学术

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

Published:2022-05-12 Issue:8 Volume:12 Page:1904-1921
ISSN:2159-8274
Container-title:Cancer Discovery
language:en
Short-container-title:

Author:

Chae Chang-Suk¹^ORCID,Sandoval Tito A.¹^ORCID,Hwang Sung-Min¹^ORCID,Park Eun Sil²,Giovanelli Paolo³⁴^ORCID,Awasthi Deepika¹^ORCID,Salvagno Camilla¹^ORCID,Emmanuelli Alexander¹³,Tan Chen¹,Chaudhary Vidyanath⁵,Casado Julia⁶⁷^ORCID,Kossenkov Andrew V.⁸^ORCID,Song Minkyung⁹^ORCID,Barrat Franck J.³⁵^ORCID,Holcomb Kevin¹^ORCID,Romero-Sandoval E. Alfonso¹⁰^ORCID,Zamarin Dmitriy¹¹^ORCID,Pépin David¹²¹³,D'Andrea Alan D.¹³^ORCID,Färkkilä Anniina⁶⁷^ORCID,Cubillos-Ruiz Juan R.¹³¹⁴^ORCID

Affiliation:

1. 1Department of Obstetrics and Gynecology, Weill Cornell Medicine, New York, New York.

2. 2Department of Ophthalmology, Columbia University, New York, New York.

3. 3Immunology and Microbial Pathogenesis Program, Weill Cornell Graduate School of Medical Sciences, New York, New York.

4. 4Immunology Program, Memorial Sloan Kettering Cancer Center, New York, New York.

5. 5HSS Research Institute and David Z. Rosensweig Genomics Research Center, Hospital for Special Surgery, New York, New York.

6. 6Research Program in Systems Oncology, University of Helsinki, Helsinki, Finland.

7. 7Department of Obstetrics and Gynecology, Helsinki University Hospital, Helsinki, Finland.

8. 8Center for Systems and Computational Biology, The Wistar Institute, Philadelphia, Pennsylvania.

9. 9Department of Integrative Biotechnology, College of Biotechnology and Bioengineering, and Department of Biopharmaceutical Convergence, Sungkyunkwan University, Suwon, Gyeonggi-do, Korea.

10. 10Department of Anesthesiology, Pain Mechanisms Laboratory, Wake Forest University School of Medicine, Winston-Salem, North Carolina.

11. 11Department of Medicine, Gynecologic Medical Oncology Service, Memorial Sloan Kettering Cancer Center, New York, New York.

12. 12Pediatric Surgical Research Laboratories, Massachusetts General Hospital, Boston, Massachusetts. 13Department of Surgery, Harvard Medical School, Boston, Massachusetts.

13. 14Susan F. Smith Center for Women's Cancers, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts.

14. 15Sandra and Edward Meyer Cancer Center, Weill Cornell Medicine, New York, New York.

Abstract

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

Publisher

American Association for Cancer Research (AACR)

Subject

Oncology

Link

https://aacrjournals.org/cancerdiscovery/article-pdf/doi/10.1158/2159-8290.CD-21-1181/3148681/cd-21-1181.pdf

Reference65 articles.

1. Inhibition of autotaxin delays breast tumor growth and lung metastasis in mice;Benesch;FASEB J,2014

2. Evaluation of serum ATX and LPA as potential diagnostic biomarkers in patients with pancreatic cancer;Chen;BMC Gastroenterol,2021

3. Plasma levels of lysophosphatidic acid in ovarian cancer versus controls: a meta-analysis;Li;Lipids Health Dis,2015

4. Expression of autotaxin and lysophosphatidic acid receptors increases mammary tumorigenesis, invasion, and metastases;Liu;Cancer Cell,2009

5. Lysophosphatidic acid (LPA) in malignant ascites stimulates motility of human pancreatic cancer cells through LPA1;Yamada;J Biol Chem,2004

Cited by 22 articles. 订阅此论文施引文献订阅此论文施引文献，注册后可以免费订阅5篇论文的施引文献，订阅后可以查看论文全部施引文献

1. Reprogramming of lipid metabolism in the tumor microenvironment: a strategy for tumor immunotherapy;Lipids in Health and Disease;2024-02-01

2. Limitations and potential of immunotherapy in ovarian cancer;Frontiers in Immunology;2024-01-09

3. Autotaxin–lysolipid signaling suppresses a CCL11–eosinophil axis to promote pancreatic cancer progression;Nature Cancer;2024-01-09

4. Biology-driven therapy advances in high-grade serous ovarian cancer;Journal of Clinical Investigation;2024-01-02

5. Perspective Chapter: Dendritic Cells in the Tumor Microenvironment;Tumor Microenvironment - New Insights;2023-11-22