Diversification of circulating and tumor‐infiltrating plasmacytoid DCs towards the P3 (CD80<sup>+</sup> PDL1<sup>−</sup>)‐pDC subset negatively correlated with clinical outcomes in melanoma patients

Valladeau‐Guilemond

Mouret³

et al. 2022

Front. Immunol.

Self Cite

Subversion of immunity by tumors is a crucial step for their development. Dendritic cells (DCs) are strategic immune cells that orchestrate anti-tumor immune responses but display altered functions in cancer. The bases for such DCs’ hijacking are not fully understood. Tumor cells harbor unusual glycosylation patterns of surface glycoproteins and glycolipids. DCs express glycan-binding receptors, named C-type lectin receptors (CLR), allowing them to sense changes in glycan signature of their environment, and subsequently trigger a response. Recognition of tumor glycans by CLRs is crucial for DCs to shape antitumor immunity, and decisive in the orientation of the response. Yet the status of the CLR machinery on DCs in cancer, especially melanoma, remained largely unknown. We explored CLR expression patterns on circulating and tumor-infiltrating cDC1s, cDC2s, and pDCs of melanoma patients, assessed their clinical relevance, and further depicted the correlations between CLR expression profiles and DCs’ features. For the first time, we highlighted that the CLR repertoire of circulating and tumor-infiltrating cDC1s, cDC2s, and pDCs was strongly perturbed in melanoma patients, with modulation of DCIR, CLEC-12α and NKp44 on circulating DCs, and perturbation of Dectin-1, CD206, DEC205, DC-SIGN and CLEC-9α on tumor-infiltrating DCs. Furthermore, melanoma tumor cells directly altered CLR expression profiles of healthy DC subsets, and this was associated with specific glycan patterns (Man, Fuc, GlcNAc) that may interact with DCs through CLR molecules. Notably, specific CLR expression profiles on DC subsets correlated with unique DCs’ activation status and functionality and were associated with clinical outcome of melanoma patients. Higher proportions of DCIR-, DEC205-, CLEC-12α-expressing cDCs were linked with a better survival, whereas elevated proportions of CD206-, Dectin1-expressing cDCs and NKp44-expressing pDCs were associated with a poor outcome. Thus, melanoma tumor may shape DCs’ features by exploiting the plasticity of the CLR machinery. Our study revealed that melanoma manipulates CLR pathways to hijack DC subsets and escape from immune control. It further paved the way to exploit glycan-lectin interactions for the design of innovative therapeutic strategies, which exploit DCs’ potentialities while avoiding hijacking by tumor, to properly reshape anti-tumor immunity by manipulating the CLR machinery.

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Unique CLR expression patterns on circulating and tumor-infiltrating DC subsets correlated with clinical outcome in melanoma patients

Valladeau‐Guilemond

Mouret³

et al. 2022

Front. Immunol.

Self Cite

“…However, tumor exploit DCs’ plasticity to escape immunity ( 9 , 10 ). Such subversion has been documented in melanoma ( 10 ), where cDC2s ( 11 ) and pDCs ( 12 , 13 ) display altered features, trigger pro-tumoral regulatory responses, exhibit altered cross-talk with anti-tumor immune effector cells ( 12 , 14 ), and have been associated with bad clinical outcomes. Yet, the bases for such DCs’ hijacking remains elusive.…”

Section: Introductionmentioning

confidence: 99%

The melanoma tumor glyco-code impacts human dendritic cells’ functionality and dictates clinical outcomes

Roubinet²,

Mouret³

et al. 2023

Front. Immunol.

Self Cite

Subversion of immunity is a hallmark of cancer development. Dendritic cells (DCs) are strategic immune cells triggering anti-tumor immune responses, but tumor cells exploit their versatility to subvert their functions. Tumor cells harbor unusual glycosylation patterns, which can be sensed through glycan-binding receptors (lectins) expressed by immune cells that are crucial for DCs to shape and orientate antitumor immunity. Yet, the global tumor glyco-code and its impact on immunity has not been explored in melanoma. To decrypt the potential link between aberrant glycosylation patterns and immune evasion in melanoma, we investigated the melanoma tumor glyco-code through the GLYcoPROFILE™ methodology (lectin arrays), and depicted its impact on patients’ clinical outcome and DC subsets’ functionality. Specific glycan patterns correlated with clinical outcome of melanoma patients, GlcNAc, NeuAc, TF-Ag and Fuc motifs being associated with poor outcome, whereas Man and Glc residues elicited better survival. Strikingly, tumor cells differentially impacting cytokine production by DCs harbored distinct glyco-profiles. GlcNAc exhibited a negative influence on cDC2s, whereas Fuc and Gal displayed inhibitory impacts on cDC1s and pDCs. We further identified potential booster glycans for cDC1s and pDCs. Targeting specific glycans on melanoma tumor cells restored DCs’ functionality. The tumor glyco-code was also linked to the nature of the immune infiltrate. This study unveils the impact of melanoma glycan patterns on immunity, and paves the way for innovative therapeutic options. Glycans/lectins interactions arise as promising immune checkpoints to rescue DCs from tumor’ hijacking to reshape antitumor immunity and inhibit immunosuppressive circuits triggered by aberrant tumor glycosylation.

“…In addition, Alculumbre et al showed that pDCs derived from healthy donors can differentiate into three stable subsets—distinguished by their CD80 and PD-L1 expression and possessing functional specificities—after a single stimulus [ 26 ]. These pDC subsets can also be found in autoimmune diseases (lupus and psoriasis) [ 26 ], after viral infections (SARS-CoV-2) [ 27 ], and in the context of melanoma [ 28 ].…”

Section: Different DC Subsets At Basal State and During Inflammationmentioning

confidence: 99%

“…Furthermore, the development of high throughput technologies (CyTOF, scRNA-seq) also allowed the extensive characterization of previously known DC subsets and the identification of new DC subsets (like DC3s). In the context of melanoma, several DC subsets have been shown to infiltrate the tumors [ 28 , 35 , 36 , 37 , 38 , 39 ], and—given the different functions of DC subsets—DC heterogeneity in the immune infiltrate could affect subsequent anti-tumor immunity ( Figure 1 ).…”

Section: DC Subsets In Melanoma: Heterogeneity Function Subversion An...mentioning

confidence: 99%

Dendritic Cell Subsets in Melanoma: Pathophysiology, Clinical Prognosis and Therapeutic Exploitation

Saas

Aspord

2023

Cancers

Evasion from immunity is a hallmark of cancer development. Dendritic cells (DCs) are strategic immune cells shaping anti-tumor immune responses, but tumor cells exploit DC versatility to subvert their functions. Unveiling the puzzling role of DCs in the control of tumor development and mechanisms of tumor-induced DC hijacking is critical to optimize current therapies and to design future efficient immunotherapies for melanoma. Dendritic cells, crucially positioned at the center of anti-tumor immunity, represent attractive targets to develop new therapeutic approaches. Harnessing the potencies of each DC subset to trigger appropriate immune responses while avoiding their subversion is a challenging yet promising step to achieve tumor immune control. This review focuses on advances regarding the diversity of DC subsets, their pathophysiology and impact on clinical outcome in melanoma patients. We provide insights into the regulation mechanisms of DCs by the tumor, and overview DC-based therapeutic developments for melanoma. Further insights into DCs’ diversity, features, networking, regulation and shaping by the tumor microenvironment will allow designing novel effective cancer therapies. The DCs deserve to be positioned in the current melanoma immunotherapeutic landscape. Recent discoveries strongly motivate exploitation of the exceptional potential of DCs to drive robust anti-tumor immunity, offering promising tracks for clinical successes.