Dr. Elise Chiffoleau
Centre de Recherche en Transplantation et Immunologie,
Institut Transplantation Urologie Néphrologie,
CHU Hôtel-Dieu, Nantes, France
Role of the C-type lectin-like receptor CLEC-1 in dendritic cells and anti-tumor response
It is largely established now that tumors evolve to escape antitumor immunity by promoting an immunosuppressive microenvironment that exploits numerous inhibitory checkpoints. Immune checkpoint molecules are crucial to maintain self-tolerance and modulate the length and magnitude of effector immune responses in peripheral tissues in order to minimize collateral tissue damage.
The critical roles of these inhibitory checkpoints in obstructing antitumor immunity have been illustrated by the remarkable success of the blockade with antibodies (Abs) of the T-cell immune checkpoint PD-1/PD-L1. Despite this, a significant percentage of patients do not respond or develop resistance.
Therefore, eliciting effective antitumor immune responses in patients who fail checkpoint inhibitor therapy is a critical challenge in cancer immunotherapy, and in such patients, myeloid cells are promising therapeutic targets. Indeed, as the major tumor-infiltrating immune cell population, myeloid cells are commonly educated by tumor cells to become their partners in crime, promoting tumor immune escape, angiogenesis, tumor growth, and metastasis. Interestingly, these past few years, literature demonstrates that tumor hijacks physiological mechanisms of C-type lectin receptors (CLRs) that normally restrain immune cell–mediated tissue damage to suppress myeloid cell activation and promote tumor immune evasion. CLRs were primary described to couple innate and adaptive immunity for host defense. However, theses receptors have also recently emerged as orchestrators of sterile inflammation by sensing cellular molecules exposed only by stressed, infected, malignant, or dead cells. Of particular interest, are the C-type lectin-like receptors (CTLRs) of the dectin family that are able to recognize carbohydrates but also more diverse ligands such as lipids and proteins (1-2). CTLRs are able to internalize antigens for subsequent presentation to T-cells, and by triggering secretion of particular set of cytokines and chemokines, finely polarize subsequent Th differentiation. Interestingly, in our Center of Research for Transplantation and Immunology (CRTI), we previously identified the CTLR CLEC-1 as highly expressed by myeloid cells in a model of allograft tolerance in rat (3). We demonstrated that CLEC-1 is expressed by monocytes, macrophages, dendritic cells (DCs) and neutrophils and is enhanced by the immunosuppressive cytokine TGFβ to inhibit downstream CD4+ Th1 and Th17 responses (3-4). Knowing that tumor immune escape and graft tolerance share similar mechanisms, we started to investigate implication of CLEC-1 in anti-tumor response. Interestingly, our preliminary data demonstrate that CLEC-1 is highly expressed by myeloid suppressive cells from human tumors. Moreover, in experimental models of cancer, CLEC-1 deficient rodents are better resistant to tumor development by promoting a pro-inflammatory state of myeloid cells.
Thus, our hypothesis is that the receptor CLEC-1, conferring suppressive activity in myeloid cells, may represent an original immune checkpoint target in cancer.
- (1) Chiffoleau E. C-Type Lectin-Like Receptors As Emerging Orchestrators of Sterile Inflammation Represent Potential Therapeutic Targets. Front Immunol (2018) 9:227. doi:10.3389/FIMMU.2018.00227
- (2) Drouin M, Saenz J and Chiffoleau E. C-Type Lectin-Like Receptors: Head or Tail in Cell Death Immunity. Front Immunol (2020) 11:251. doi:10.3389/fimmu.2020.00251
- (3) Thebault P, Lhermite N, Tilly G, Le Texier L, Quillard T, Heslan M, et al. The C-type lectin-like receptor CLEC-1, expressed by myeloid cells and endothelial cells, is up-regulated by immunoregulatory mediators and moderates T cell activation. J Immunol. 2009 Sep 1;183(5):3099-108.
- (4) Lopez Robles MD, Pallier A, Huchet V, Le Texier L, Remy S, Braudeau C, et al. Cell-surface C-type lectin-like receptor CLEC-1 dampens dendritic cell activation and downstream Th17 responses. Blood Advances. 2017;1(9):557-68
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