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

Abstract

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.

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

“…Further investigating the underlying mechanism of the glycanmediated effect on DCs would be very relevant. In our previous work (32), we documented a link between glycan motifs on tumor cells and perturbed CLR profiles on tumor-infiltrating DC subsets. The glycoprofile of primary melanoma tumor cell lines revealed high level of Man, Fuc and GlcNAc motifs.…”

“…These motifs are known to be recognized by Dectin 1 (specific for β-glucans), DCIR, DC-SIGN and CD206 (specific for Man, Fuc and GlcNAc motifs). Strikingly, these CLRs are the one that were the most modulated on tumor-infiltrating DC subsets from melanoma patients ( 32 ). We highlighted strong link between specific glycans and corresponding CLR on DCs within the tumor of melanoma patients.…”

“…The aberrant glycosylation of melanoma tumor cells could alter DCs’ features through CLR signaling and subsequently subvert anti-tumor immune responses. We recently highlighted that the CLR profiles on circulating and tumor-infiltrating DC subsets displayed strong perturbations in melanoma patients, correlated with unique DCs’ activation status and functionality, and dictated clinical outcomes ( 32 ). Furthermore, melanoma tumor cells directly altered CLR expression profiles of healthy DC subsets, suggesting that they displayed and released glycan motifs that may interact with DCs through CLR molecules.…”

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

“…Emerging evidence suggest in a few cancer types an immunosuppressive role of altered tumor glycosylation on innate immune responses through modulation of immune cells’ function [ 100 ]. In melanoma patients, we recently highlighted that the CLR profiles in circulating and tumor-infiltrating DC subsets display strong perturbations, correlated with unique DCs’ features, and dictated clinical outcomes [ 101 ]. Furthermore, the melanoma tumor glycocode directly affects the DC subsets’ functionality [ 102 ], revealing the glycan/CLR axis as a potential DC subversion pathway in melanoma.…”

Melanoma tumour‐derived glycans hijack dendritic cell subsets through C‐type lectin receptor binding

“…These two DC subsets trigger pro-tumour regulatory responses, exhibit altered crosstalk with anti-tumour immune effector cells [19,20], and have been associated with poor clinical outcome. We previously revealed that circulating and tumour-infiltrating DCs from melanoma patients display major perturbations in their CLR expression profiles [21]. Furthermore, melanoma hijacks DCs by secreting immunosuppressive factors (e.g., gangliosides, interleukin [IL]-6, IL-10, transforming growth factor-β, prostaglandin-E2) and immunomodulatory molecules (e.g., thymus-and activation-regulated chemokine [TARC]/CC chemokine ligand [CCL]17, macrophagederived chemokine [MDC]/CCL22) [19], by inducing metabolic stress which interferes with DC differentiation, recruitment, maturation and function, or also by promoting regulatory responses and Th2 polarisation [22,23].…”