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

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.

BDCA1+ cDC2s, BDCA2+ pDCs and BDCA3+ cDC1s reveal distinct pathophysiologic features and impact on clinical outcomes in melanoma patients

“…37 In line with our data, high expression of cDC1s transcriptomic signature in various tumor microenvironments correlated with a better clinical outcome 30,51 including melanoma. 53,56 Importantly, we uncovered that the proportion of cDC1s in the blood was the most accurate parameter to predict clinical outcome of melanoma patients (na€ ıve of treatment by immunotherapies). This novelty could be very useful to optimise disease management and better orientate decisions by clinicians to define the best treatment leading to increased clinical success.…”

Functional Role of Dendritic Cell Subsets in Cancer Progression and Clinical Implications

“…The analysis of a large cohort of breast primary tumors highlighted the selective role of cDC1-derived IFN-lamba1 in the generation of a microenvironment rich of Th1-cytokines and chemokines active on cytotoxic lymphocytes. Both IFN-lamba1 and its receptor were associated with favorable patient outcomes [149].…”

Harnessing the Complete Repertoire of Conventional Dendritic Cell Functions for Cancer Immunotherapy

“…In particular, human cDC1 responded by IFNλ2 (IL-28A) and IFNλ1 (IL-29) secretion after stimulation with poly(I:C) [ 573 ]. A recent study indicated that cDC1-dependent IFNλ signatures, in particular of IFNλ1 (IL-29) and its receptor, were associated with superior disease outcomes in breast cancer [ 593 ]. This might be explainable by the capacity of IFNλ to drive a Th1 environment via boosting production of IL-12, IFNγ and cytotoxic CD8 + T cell-recruiting cytokines [ 593 ].…”

“…A recent study indicated that cDC1-dependent IFNλ signatures, in particular of IFNλ1 (IL-29) and its receptor, were associated with superior disease outcomes in breast cancer [ 593 ]. This might be explainable by the capacity of IFNλ to drive a Th1 environment via boosting production of IL-12, IFNγ and cytotoxic CD8 + T cell-recruiting cytokines [ 593 ]. On top, this study showed that TLR3 ligation allows for kick-starting IFNλ responses by tumor-associated cDC1 [ 593 ].…”

“…This might be explainable by the capacity of IFNλ to drive a Th1 environment via boosting production of IL-12, IFNγ and cytotoxic CD8 + T cell-recruiting cytokines [ 593 ]. On top, this study showed that TLR3 ligation allows for kick-starting IFNλ responses by tumor-associated cDC1 [ 593 ]. Finally, murine cDC1 or cDC2 were shown to mount cytotoxic CD8 + T cell responses via IL-27 following stimulation with poly(I:C) (TLR3 ligand) or R848 (TLR7 ligand), respectively [ 162 ].…”