Human Plasmacytoid Dendritic Cells and Cutaneous Melanoma

Monti, Matilde; Consoli, Francesca; Vescovi, Raffaella; Bugatti, Mattia; Vermi, William

doi:10.3390/cells9020417

Cited by 27 publications

(40 citation statements)

References 287 publications

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“…DCs are endowed with a high functional plasticity allowing them to orientate immune responses towards diverse profiles depending on the microenvironment. Tumors exploit such versatility of DCs through suppressive pathways to subvert DC functions and escape immunity 22‐25 . Despite evidence of tumor infiltration by the three DC subsets, 26‐30 their precise pathophysiologic role remains unclear.…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2020

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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.

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Section: Introductionmentioning

confidence: 99%

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

et al. 2020

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“…As previously reported, circulating pDCs are reduced in various human cancer patients compared to healthy subjects, particularly in the advanced stage of disease [ 35 ]. By flow cytometry on fresh whole blood, we previously documented the collapse of pDC and myeloid DC (mDC) subsets in advanced MM [ 29 ].…”

Section: Resultsmentioning

confidence: 67%

“…The frequency of circulating pDCs is dramatically reduced in melanoma patients with systemic spread [ 29 , 52 , 53 ], but their clinical significance as well as their functional state have been poorly characterized [ 35 ]. Findings from retrospective analysis are conflicting [ 35 ]. This study reports the analysis of the circulating pDCs in a prospective chemo-naïve MM patient cohort.…”

Section: Discussionmentioning

confidence: 99%

Plasmacytoid Dendritic Cell Impairment in Metastatic Melanoma by Lactic Acidosis

Monti

Vescovi

Consoli

et al. 2020

Cancers

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The introduction of targeted therapies and immunotherapies has significantly improved the outcome of metastatic melanoma (MM) patients. These approaches rely on immune functions for their anti-melanoma response. Plasmacytoid dendritic cells (pDCs) exhibit anti-tumor function by production of effector molecules, type I interferons (I-IFNs), and cytokines. Tissue and blood pDCs result compromised in MM, although these findings are still partially conflicting. This study reports that blood pDCs were dramatically depleted in MM, particularly in patients with high lactate dehydrogenase (LDH) and high tumor burden; the reduced pDC frequency was associated with poor overall survival. Circulating pDCs resulted also in significant impairment in interferon alpha (IFN-α) and C-X-C motif chemokine 10 (CXCL10) production in response to toll-like receptor (TLR)-7/8 agonists; on the contrary, the response to TLR-9 agonist remained intact. In the BRAFV600+ subgroup, no recovery of pDC frequency could be obtained by BRAF and MEK inhibitors (BRAFi; MEKi), whereas their function was partially rescued. Mechanistically, in vitro exposure to lactic acidosis impaired both pDC viability and function. In conclusion, pDCs from MM patients were found to be severely impaired, with a potential role for lactic acidosis. Short-term responses to treatments were not associated with pDC recovery, suggesting long-lasting effects on their compartment.

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“…Some have suggested that the addition of novel innate cell-based therapies could overcome radiation-induced immunosuppressive effects [35] through their activation of Toll-like receptors. One such receptor, TLR9, is expressed in pDCs and stimulates antitumor immunity by producing IFNs [36] . Mature pDCs are also known to prime antigen-specific T-cell immunity through response to a variety of DNA and RNA viruses [37] .…”

Section: Discussionmentioning

confidence: 99%

Addition of TLR9 agonist immunotherapy to radiation improves systemic antitumor activity

Younes

Barsoumian

Sezen

et al. 2021

Translational Oncology

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Highlights High-dose RT upregulated pDCs within the tumor microenvironment. The administration of intratumoral TLR9 agonist (CMP-001) after stereotactic RT significantly enhanced the anti-tumor immune response both locally and at secondary tumor site. CMP-001 Post-RT delayed the abscopal tumor growth and extended the survival rate via increasing the percentages of activated CD4 + and CD8 + T-cells within the tumor microenvironment. The treatment proved efficacious in both lung adenocarcinoma and colon carcinoma syngeneic models used.

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Human Plasmacytoid Dendritic Cells and Cutaneous Melanoma

Cited by 27 publications

References 287 publications

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

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

Plasmacytoid Dendritic Cell Impairment in Metastatic Melanoma by Lactic Acidosis

Addition of TLR9 agonist immunotherapy to radiation improves systemic antitumor activity

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Human Plasmacytoid Dendritic Cells and Cutaneous Melanoma

Cited by 27 publications

References 287 publications

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

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

Plasmacytoid Dendritic Cell Impairment in Metastatic Melanoma by Lactic Acidosis

Addition of TLR9 agonist immunotherapy to radiation improves systemic antitumor activity

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Product

Resources

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

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