Periodic Reporting for period 1 - MCNTMTDC (Metabolic control on NF-κB activity during dendritic cells-mediated immune tolerance to tumours)
Reporting period: 2017-09-01 to 2019-08-31
NF-κB signalling has been reported to play a prominent role in DC activation under proinflammatory conditions and also suggested to be required for homeostatic maturation of dendritic cells to maintain peripheral tolerance. This project aims at deciphering the role of NF-κB signalling in cDC1 to fight against cancer. Our findings revealed that NF-κB in cDC1s majorly impacts anti-tumour immunity through excluding the recruitment of cytotoxic T cells to tumour sites. Moreover, our study unravel another signalling pathway controlled by NF-κB in tunour-associated cDC1s than control the tumour growth through the recruitment of cytotoxic T cells.
These findings constitute a breakthrough in onco-immunology field because they answer to important questions that could help cancer patients to better respond to immunotherapies.
The adaptive immune response to tumours is regulated by an intimate balance between tolerogenic and immunogenic responses to tumour associated antigens. DCs are key regulators of both protective immune responses and peripheral tolerance. A minor population of DCs, conventional DCs type 1 (cDC1s), is recognized within tumour micro-environment as a key player in the control of cancer by adaptive immunity. They are central inducers of tumourassociated CD8+ T cell response through their ability to present antigenic peptides on major histocompatibility complex I (MHC-I) following activation/maturation in tumour microenvironment. This subset of DCs are CD8α+ and uniquely express a cell surface marker XCR1. Although their role in the control of cancer by adaptive immunity is well documented now, the signalling pathways that govern their tumour-related functions are poorly understood.
NF-κB signalling has been reported to play a prominent role in DC activation under proinflammatory conditions and also suggested to be required for homeostatic maturation of DCs to maintain peripheral tolerance. In order to dissect the role of NF-κB signalling in tumour-associated cDC1s, we generated mice with a targeted deletion of IκB kinase β (IKKβ) – a subunit of the IKK complex that is crucial for canonical activation of NF-κB6 – in XCR1+ DCs lineage and determined its effect on DC function in steady-state and upon engraftment of C57Bl/6J isogenic BrafV600E/+Pten-/-Cdkn2a-/- mouse melanoma cell line (termed
YUMM 1.7). Our findings revealed that IKKβ deletion in XCR1+ DCs partially affects their homeostatic maturation under steady-state conditions and majorly impacts anti-tumour immunity through excluding the recruitment of cytotoxic CD8+ T cells to tumour sites.
Transcriptomic assessment of these tumour associated-XCR1+ DCs identified a gene network dependent not only on NF-kB, but also on the Interferon Regulatory Factor 1 (IRF1) signalling that includes chemokine genes specialized in the recruitment of CD8+ T cells. This gene signature, specially the one regulated by IRF1, appears to be under the control of Interferon-γ (IFN-γ), which is prominent in the tumour-microenvironment. Of note, IRF1 deletion in XCR1+ DCs shows similar phenotype as IKKβ deletion in the YUMM 1.7 melanoma model resulting in dis-controlled tumour growth associated with a disruption of CD8+ T cells
recruitment to tumours and activation against YUMM tumour-associated antigens.
These data unravel NF-κB and IRF1 as drivers of key pathways for cDC1 function in tumour micro-environment. This innovative concept represents potential target in optimized treatment regimens against cancer.
Furthermore, to get insight into the impact of NFkB/IRF1-regulated transcription in cDC1s from melanoma patients, we are deconvoluting the data from The Cancer Genome Atlas of the skin cutaneous melanoma database to assess assess the prognostic value of cDC1s highly correlated with NFkB/IRF1 pathway by correlating of NFkB/IRF1pathway with cDC1 signatures in tumour samples and analysing the survival of the patients associated with this study.