N-MYC impairs innate immune signaling in high-grade serous ovarian carcinoma

Alex Miranda, Swetansu Pattnaik, Phineas T. Hamilton, Monica Alvaro Fuss, Shreena Kalaria, Céline M. Laumont, Julian Smazynski, Monica Mesa, Allyson Banville, Xinpei Jiang, Russell Jenkins, Israel Cañadas, Brad H. Nelson

Research output: Contribution to journalArticlepeer-review

Abstract

High-grade serous ovarian cancer (HGSC) is a challenging disease, especially for patients with immunologically “cold” tumors devoid of tumor-infiltrating lymphocytes (TILs). We found that HGSC exhibits among the highest levels of MYCNexpression and transcriptional signature across human cancers, which is strongly linked to diminished features of antitumor immunity. N-MYC repressed basal and induced IFN type I signaling in HGSC cell lines, leading to decreased chemokine expression and T cell chemoattraction. N-MYC inhibited the induction of IFN type I by suppressing tumor cell–intrinsic STING signaling via reduced STING oligomerization, and by blunting RIG-I–like receptor signaling through inhibition of MAVS aggregation and localization in the mitochondria. Single-cell RNA sequencing of human clinical HGSC samples revealed a strong negative association between cancer cell–intrinsic MYCN transcriptional program and type I IFN signaling. Thus, N-MYC inhibits tumor cell–intrinsic innate immune signaling in HGSC, making it a compelling target for immunotherapy of cold tumors.

Original languageEnglish
Article numbereadj5428
Pages (from-to)eadj5428
JournalScience Advances
Volume10
Issue number20
DOIs
StatePublished - May 2024

Keywords

  • Adaptor Proteins, Signal Transducing/metabolism
  • Cell Line, Tumor
  • Cystadenocarcinoma, Serous/pathology
  • Female
  • Gene Expression Regulation, Neoplastic
  • Humans
  • Immunity, Innate
  • Interferon Type I/metabolism
  • Membrane Proteins/metabolism
  • Neoplasm Grading
  • Ovarian Neoplasms/immunology
  • Proto-Oncogene Proteins c-myc/metabolism
  • Signal Transduction

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