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Updated: May 28, 2025

A Robust Discovery Platform for the Identification of Novel Mediators of Melanoma Metastasis
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A Robust Discovery Platform for the Identification of Novel Mediators of Melanoma Metastasis

Published on: March 8, 2022

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Genomic mediators of acquired resistance to immunotherapy in metastatic melanoma

Julia Schiantarelli1, Mouadh Benamar1, Jihye Park1

  • 1Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115, USA; Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA.

Cancer Cell
|February 11, 2025
PubMed

Insights

Most patients with metastatic melanoma resist immune checkpoint inhibitors (ICIs). This study identifies mutations in SEC24C/D, impacting STING signaling, as a novel mechanism of acquired resistance to ICIs.

Area of Science:

  • Oncology
  • Immunology
  • Genetics

Background:

  • Immune checkpoint inhibitors (ICIs) offer durable responses in some metastatic melanoma patients.
  • However, most patients develop intrinsic or acquired resistance to ICIs, necessitating identification of resistance mechanisms.

Purpose of the Study:

  • To identify novel mediators of acquired resistance to ICIs in metastatic melanoma.
  • To investigate the role of SEC24C/D mutations in regulating STING signaling and anti-tumor immunity.

Main Methods:

  • Somatic genomic profiling of matched pre-treatment and post-resistance tumor biopsies from 25 metastatic melanoma patients.
  • Functional characterization of SEC24C mutations in engineered melanoma cells.

Main Results:

  • Acquired resistance tumors showed defects in B2M or JAK1/2.
  • Mutations in SEC24C and SEC24D were identified in 3 patients, associated with acquired resistance.
  • Engineered melanoma cells with SEC24C mutations exhibited impaired STING signaling, reduced type I interferon production, and decreased cytotoxic T-cell activation.

Conclusions:

  • Aberrant STING trafficking due to SEC24C/D mutations is nominated as a novel mechanism of acquired resistance to ICIs in melanoma.
  • Understanding these mechanisms could lead to new therapeutic strategies for overcoming ICI resistance.
Keywords:
SEC24STING signalingacquired resistanceimmune checkpoint inhibitorsmetastatic melanoma

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