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.

Type 1 conventional dendritic cells and interferons are required for spontaneous CD4+ and CD8+ T‐cell protective responses to breast cancer

“…and Hubert et al 13 . Hence, cDC1 represent an attractive target for new generation cancer immunotherapies 3,10,11,13–22 . Yet, most of the studies that investigated the antitumor role of cDC1 in vivo used mutant mice whose deficiencies were not affecting exclusively cDC1.…”

“… 13 Hence, cDC1 represent an attractive target for new generation cancer immunotherapies. 3 , 10 , 11 , 13 , 14 , 15 , 16 , 17 , 18 , 19 , 20 , 21 , 22 Yet, most of the studies that investigated the antitumor role of cDC1 in vivo used mutant mice whose deficiencies were not affecting exclusively cDC1. Irf8 deficiency in CD11c‐expressing cells also affected the differentiation and functions of plasmacytoid dendritic cells 23 and inflammatory cDC2.…”

Clinical Significance of Tumor-Infiltrating Conventional and Plasmacytoid Dendritic Cells in Pancreatic Ductal Adenocarcinoma

“…Furthermore, higher expressions of cDC1-associated gene signatures were significantly associated with prolonged OS in patients with breast cancer, colorectal cancer, head and neck squamous cell carcinoma (HNSCC), lung adenocarcinoma, skin cutaneous melanoma, and ovarian cancer [ 19 , 20 , 21 , 22 ]. Moreover, a high frequency of melanoma-infiltrating CD40 + cDC1s predicted improved OS [ 23 ].…”

“…Higher expression of specific gene signatures for cDC2s was linked to better prognosis of patients with HNSCC, invasive breast carcinoma, lung adenocarcinoma, and skin cutaneous metastatic melanoma [ 20 ]. Conversely, a higher frequency of tumor-associated cDC2s was correlated with reduced OS in non-small cell lung cancer [ 26 ] and worse progression-free survival (PFS) of melanoma patients [ 23 ].…”

“…Enhanced expression of pDC-specific genes was associated with prolonged OS in HNSCC, papillary renal cell carcinoma, and lung adenocarcinoma [ 20 ]. Moreover, high levels of tumor-infiltrating CD86 + pDCs predicted prolonged PFS of melanoma patients [ 23 ]. More recently, we have shown that a higher density of tumor-associated pDCs is linked to improved PFS and OS of colon cancer patients [ 30 ].…”