Dataset Information

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

ABSTRACT: Objectives: Dendritic cells play a pivotal but still enigmatic role in the control of tumor development. Composed of specialised subsets (cDC1s, cDC2s, pDCs), DCs are critical in triggering and shaping antitumor immune responses. Yet, tumors exploit plasticity of DCs to subvert their functions and escape from immune control. This challenging controversy prompted us to explore the pathophysiological role of cDCs and pDCs in melanoma, where their precise and coordinated involvement remains to be deciphered.

Methods: We investigated in melanoma patients the phenotypic and functional features of circulating and tumor-infiltrating BDCA1⁺ cDC2s, BDCA2⁺ pDCs and BDCA3⁺ cDC1s and assessed their clinical impact.

Results: Principal component analyses (PCA) based on phenotypic or functional parameters of DC subsets revealed intra-group clustering, highlighting specific features of DCs in blood and tumor infiltrate of patients compared to healthy donors. DC subsets exhibited perturbed frequencies in the circulation and actively infiltrated the tumor site, while harbouring a higher activation status. Whereas cDC2s and pDCs displayed an altered functionality in response to TLR triggering, circulating and tumor-infiltrating cDC1s preserved potent competences associated with improved prognosis. Notably, the proportion of circulating cDC1s predicted the clinical outcome of melanoma patients.

Conclusion: Such understanding uncovers critical and distinct impact of each DC subset on clinical outcomes and unveils fine-tuning of interconnections between DCs in melanoma. Elucidating the mechanisms of DC subversion by tumors could help designing new therapeutic strategies exploiting the potentialities of these powerful immune players and their cross-talks, while counteracting their skewing by tumors, to achieve immune control and clinical success.

SUBMITTER: Sosa Cuevas E

PROVIDER: S-EPMC7684973 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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Publications

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

Sosa Cuevas Eleonora E Ouaguia Laurissa L Mouret Stephane S Charles Julie J De Fraipont Florence F Manches Olivier O Valladeau-Guilemond Jenny J Bendriss-Vermare Nathalie N Chaperot Laurence L Aspord Caroline C

Clinical & translational immunology 20201124 11

<h4>Objectives</h4>Dendritic cells play a pivotal but still enigmatic role in the control of tumor development. Composed of specialised subsets (cDC1s, cDC2s, pDCs), DCs are critical in triggering and shaping antitumor immune responses. Yet, tumors exploit plasticity of DCs to subvert their functions and escape from immune control. This challenging controversy prompted us to explore the pathophysiological role of cDCs and pDCs in melanoma, where their precise and coordinated involvement remains ...[more]

PMID: 33282290

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Project description:Background and aims: Chronic hepatitis B virus (HBV) infection is a major health burden potentially evolving toward cirrhosis and hepatocellular carcinoma. HBV physiopathology is strongly related to the host immunity, yet the mechanisms of viral evasion from immune-surveillance are still misunderstood. The immune response elicited at early stages of viral infection is believed to be important for subsequent disease outcome. Dendritic cells (DCs) are crucial immune sentinels which orchestrate antiviral immunity, which offer opportunity to pathogens to subvert them to escape immunity. Despite the pivotal role of DCs in orientating antiviral responses and determining the outcome of infection, their precise involvement in HBV pathogenesis is not fully explored. Methods: One hundred thirty chronically HBV infected patients and 85 healthy donors were enrolled in the study for blood collection, together with 29 chronically HBV infected patients and 33 non-viral infected patients that were included for liver biopsy collection. In a pioneer way, we investigated the phenotypic and functional features of both circulating and intrahepatic BDCA1+ cDC2, BDCA2+ pDCs, and BDCA3+ cDC1 simultaneously in patients with chronic HBV infection by designing a unique multi-parametric flow cytometry approach. Results: We showed modulations of the frequencies and basal activation status of blood and liver DCs associated with impaired expressions of specific immune checkpoints and TLR molecules on circulating DC subsets. Furthermore, we highlighted an impaired maturation of circulating and hepatic pDCs and cDCs following stimulation with specific TLR agonists in chronic HBV patients, associated with drastic dysfunctions in the capacity of circulating DC subsets to produce IL-12p70, TNF?, IFN?, IFN?1, and IFN?2 while intrahepatic DCs remained fully functional. Most of these modulations correlated with HBsAg and HBV DNA levels. Conclusion: We highlight potent alterations in the distribution, phenotype and function of all DC subsets in blood together with modulations of intrahepatic DCs, revealing that HBV may hijack the immune system by subverting DCs. Our findings provide innovative insights into the immuno-pathogenesis of HBV and the mechanisms of virus escape from immune control. Such understanding is promising for developing new therapeutic strategies restoring an efficient immune control of the virus.

Dataset Information

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

Publications

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

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