Concerted BAG3 and SIRPα blockade impairs pancreatic tumor growth

Margot De Marco, Vanessa Gauttier, Sabrina Pengam, Caroline Mary, Bianca Ranieri, Anna Basile, Michela Festa, Antonia Falco, Francesca Reppucci, Anna Lisa Cammarota, Fausto Acernese, Vincenzo De Laurenzi, Gianluca Sala, Sergio Brongo, Masayuki Miyasaka, Shabnam Shalapour, Bernard Vanhove, Nicolas Poirier, Roberta Iaccarino, Michael KarinMaria Caterina Turco, Alessandra Rosati, Liberato Marzullo

Research output: Contribution to journalArticlepeer-review


The BAG3- and SIRPα- mediated pathways trigger distinct cellular targets and signaling mechanisms in pancreatic cancer microenvironment. To explore their functional connection, we investigated the effects of their combined blockade on cancer growth in orthotopic allografts of pancreatic cancer mt4–2D cells in immunocompetent mice. The anti-BAG3 + anti-SIRPα mAbs treatment inhibited (p = 0.007) tumor growth by about the 70%; also the number of metastatic lesions was decreased, mostly by the effect of the anti-BAG3 mAb. Fibrosis and the expression of the CAF activation marker α-SMA were reduced by about the 30% in animals treated with anti-BAG3 mAb compared to untreated animals, and appeared unaffected by treatment with the anti-SIRPα mAb alone; however, the addition of anti-SIRPα to anti-BAG3 mAb in the combined treatment resulted in a > 60% (p < 0.0001) reduction of the fibrotic area and a 70% (p < 0.0001) inhibition of CAF α-SMA positivity. Dendritic cells (DCs) and CD8+ lymphocytes, hardly detectable in the tumors of untreated animals, were modestly increased by single treatments, while were much more clearly observable (p < 0.0001) in the tumors of the animals subjected to the combined treatment. The effects of BAG3 and SIRPα blockade do not simply reflect the sum of the effects of the single blockades, indicating that the two pathways are connected by regulatory interactions and suggesting, as a proof of principle, the potential therapeutic efficacy of a combined BAG3 and SIRPα blockade in pancreatic cancer.

Original languageEnglish (US)
Article number94
JournalCell Death Discovery
Issue number1
StatePublished - Dec 2022

ASJC Scopus subject areas

  • Immunology
  • Cellular and Molecular Neuroscience
  • Cell Biology
  • Cancer Research


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