Frontiers in Immunology (Jan 2024)

Inhibition of anti-tumor immunity by melanoma cell-derived Activin-A depends on STING

  • Katarina Pinjusic,
  • Giovanna Ambrosini,
  • Giovanna Ambrosini,
  • Joao Lourenco,
  • Nadine Fournier,
  • Christian Iseli,
  • Christian Iseli,
  • Nicolas Guex,
  • Nicolas Guex,
  • Olga Egorova,
  • Sina Nassiri,
  • Daniel B. Constam

DOI
https://doi.org/10.3389/fimmu.2023.1335207
Journal volume & issue
Vol. 14

Abstract

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The transforming growth factor-β (TGF-β) family member activin A (hereafter Activin-A) is overexpressed in many cancer types, often correlating with cancer-associated cachexia and poor prognosis. Activin-A secretion by melanoma cells indirectly impedes CD8+ T cell-mediated anti-tumor immunity and promotes resistance to immunotherapies, even though Activin-A can be proinflammatory in other contexts. To identify underlying mechanisms, we here analyzed the effect of Activin-A on syngeneic grafts of Braf mutant YUMM3.3 mouse melanoma cells and on their microenvironment using single-cell RNA sequencing. We found that the Activin-A-induced immune evasion was accompanied by a proinflammatory interferon signature across multiple cell types, and that the associated increase in tumor growth depended at least in part on pernicious STING activity within the melanoma cells. Besides corroborating a role for proinflammatory signals in facilitating immune evasion, our results suggest that STING holds considerable potential as a therapeutic target to mitigate tumor-promoting Activin-A signaling at least in melanoma.

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