Research ArticleTUMOR IMMUNOLOGY

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

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Science Immunology  17 Apr 2020:
Vol. 5, Issue 46, eaav3942
DOI: 10.1126/sciimmunol.aav3942

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cDC1 and cancer

The conventional dendritic cell 1 (cDC1) subset has been shown to play a critical role in antitumor responses, and here, Hubert et al. show that human cDC1 contribute to antitumor responses through production of type III interferon (also known as IFN-λ). They analyzed primary breast tumors and publicly available transcriptomic data and pinpointed IFN-λ1 production by cDC1 as being associated with favorable patient outcomes, and this cytokine promoted a microenvironment with TH1-associated cytokines and chemokines. By treating breast cell tumor suspensions with a TLR3 agonist, they were able to induce TH1-polarized responses and IFN-λ1 production by cDC1. These findings provide insight into how cDC1 cells contribute to antitumor immunity and how they might be targeted for potential therapeutic strategies.

Abstract

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.

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