IFN-III is selectively produced by cDC1 and predicts good clinical outcome in breast cancer

Margaux Hubert (1) , Elisa Gobbini (1, 2) , Coline Couillault (1) , Thien-Phong Vu Manh (3) , Anne-Claire Doffin (1) , Justine Berthet (1) , Céline Rodriguez (1) , Vincent Ollion (1) , Janice Kielbassa (4) , Christophe Sajous (5) , Isabelle Treilleux (5) , Olivier Tredan (5) , Bertrand Dubois (1) , Marc Dalod (3) , Nathalie Bendriss-Vermare (1, 6) , Christophe Caux (1, 6, 5) , Jenny Valladeau-Guilemond (1, 7)

1 UNICANCER/CRCL - Centre de Recherche en Cancérologie de Lyon
2 CHU - Centre Hospitalier Universitaire [Grenoble]
3 CIML - Centre d'Immunologie de Marseille - Luminy
4 Synergie Lyon Cancer [Lyon]
5 Centre Léon Bérard [Lyon]
6 LabEx DEVweCAN - Développement Cancer et Thérapies Ciblées [Lyon]
7 Labex_IRMIA - Institut de Recherche en Mathématiques, Interactions et Applications

Dendritic cells play a key role in the orchestration of antitumor immune responses. The cDC1 (conventional dendritic cell 1) subset has been shown to be essential for antitumor responses and response to immunotherapy, but its precise role in humans is largely unexplored. Using a multidisciplinary approach, we demonstrate that human cDC1 play an important role in the antitumor immune response through their capacity to produce type III interferon (IFN-λ). By analyzing a large cohort of breast primary tumors and public transcriptomic datasets, we observed specific production of IFN-λ1 by cDC1. In addition, both IFN-λ1 and its receptor were associated with favorable patient outcomes. We show that IFN-III promotes a TH1 microenvironment through increased production of IL-12p70, IFN-γ, and cytotoxic lymphocyte–recruiting chemokines. Last, we showed that engagement of TLR3 is a therapeutic strategy to induce IFN-III production by tumor-associated cDC1. These data provide insight into potential IFN- or cDC1-targeting antitumor therapies.

Domains: Life Sciences [q-bio]

Margaux Hubert, Elisa Gobbini, Coline Couillault, Thien-Phong Vu Manh, Anne-Claire Doffin, et al.. IFN-III is selectively produced by cDC1 and predicts good clinical outcome in breast cancer. Science Immunology, 2020, 5 (46), pp.eaav3942. ⟨10.1126/sciimmunol.aav3942⟩. ⟨hal-02998632⟩