Biology subjects

Delannoy, C.

Publications and source records attributed to Delannoy, C..

4 recordsLinked to original sources

bioRxiv2026

Functional diversity of Vγ9Vδ2 T cells overcomes glioblastoma state plasticity and antigen heterogeneity

Glioblastoma (GBM) is characterized by a high degree of cellular plasticity and intra-tumoral heterogeneity, which frequently leads to the failure of standard therapies, including immunotherapies. While chimeric antigen receptor (CAR) T cells offer a potent means of MHC-independent tumor recognition, their efficacy is hampered by the coexistence of distinct molecular states, gathered as proneural (PN) and mesenchymal (MES) phenotypes. Here, we demonstrate that gangliosides GD2 and O-acetylated GD2 (OAcGD2) are preferentially expressed by PN cells whereas MES cells display reduced expression due to upregulated ganglioside catabolism. Conversely, MES cells are known to exhibit high expression of stress-induced ligands recognized by V{gamma}9V{delta}2 T cells. We show that while engineering V{delta}2T cells with GD2- or OAcGD2-specific CAR enables the elimination of PN cells, it also facilitates the immune escape of MES cells in heterogeneous 3D-tumoroid models. Mechanistically, we reveal a hierarchy of receptor engagement, where CAR signaling predominates leading to the structural and functional exclusion of endogenous TCR from the immunological synapse. To address this receptor competition, we propose a strategy that leverages the functional effector diversity by combining untransduced and CAR-engineered V{delta}2T cells. This dual approach provides a dynamic safety net by ensuring the simultaneous elimination of PN and MES cells and preventing the selective outgrowth of resistant cells. Our findings establish a conceptual framework for designing off-the-shelf immunotherapies tailored to the metabolic and phenotypic plasticity of resistant solid tumors.

cancer biology↗

bioRxiv2024

Anemonefish use sialic acid metabolism as Trojan horse to avoid giant sea anemone stinging

Anemonefish association with giant sea anemone is an iconic example of mutualistic symbiosis. Living inside the sea anemone without triggering the firing of highly toxic nematocysts present at the surface of sea anemone tentacles provides a unique shelter to the fish, which in return, by its territorial aggressiveness, protects the sea anemone from predators. The mechanisms by which the fish avoids triggering nematocysts discharge remain elusive. One hypothesis proposes that absence of sialic acids might disable nematocysts discharge. Here, we verified four predictions about the role of sialic acids in anemonefish protection: (i) sialic acid levels are lower in anemonefish mucus than in non-symbiotic and sensitive damselfish mucus; (ii) this decrease is specific to mucus and not observed in other organs; (iii) during post-embryonic development the levels of sialic acids are inversely correlated with the level of protection; (iv) the levels of sialic acids are minimal in sea anemone mucus. Taken together, our results allow us to propose a general model, in which anemonefish specifically regulates the level of sialic acids in their mucus to avoid nematocysts discharge. Our analysis also highlights several genes implicated in sialic acid removal as potential targets for allowing protection. Interestingly, our results also suggest that unrelated juveniles of damselfish (Dascyllus trimaculatus) capable to live in proximity with giant sea anemone may use the same mechanisms. Altogether, our data suggest that clownfish use sialic acids as a Trojan horse system to downplay the defenses of the sea anemones and illustrate the convergent tinkering used by fish to allow a mutualistic association with their hosts. Significance statementThe mutualistic relationship between anemonefish and giant sea anemones, where the fish shelter among the anemones tentacles while defending it from predators, is a classic example of symbiosis. However, how the fish avoids triggering the anemones venomous nematocysts has remained a mystery. This study reveals that the fish decrease the levels of sialic acids in their mucus, potentially preventing nematocyst discharge. This finding shed light on the mechanisms underlying this symbiotic relationship. Moreover, the discovery that unrelated damselfish may employ similar strategies underscores the broader significance of convergent adaptations in facilitating similar mutualistic associations in marine fishes.

zoology↗

bioRxiv2022

Structural and functional analysis of natural capsid variants reveals sialic-acid independent entry of BK polyomavirus

BK Polyomavirus (BKPyV) is an opportunistic pathogen that causes nephropathy in kidney transplant recipients. The BKPyV major capsid protein, VP1, engages gangliosides, lipid-linked sialylated glycans at the cell surface, to gain entry into cells. Here, we characterise the influence of VP1 mutations observed in patients with persistent post-transplant BKPyV replication on ganglioside binding, VP1 protein structure, and the tropism of the virus in two renal cell lines: 293TT and immortalised renal tubular epithelial (RS) cells. Infectious entry of single mutants E73Q, E73A and the triple mutant A72V-E73Q-E82Q (VQQ) remained sialic acid-dependent. These three variants acquired binding to a-series gangliosides, including GD1a, although only E73Q was able to infect GD1a-supplemented LNCaP or GM95 cells. Crystal structures of the three mutants showed a clear shift of the BC2 loop in mutants E73A and VQQ that correlated with the inability of these VP1 variants to infect ganglioside complemented cells. On the other hand, the double mutant K69N-E82Q lost the ability to bind sialic acid, with the K69N mutation leading to a steric clash which precludes sialic acid binding. Nevertheless, this mutant retained significant infectivity in 293TT cells that was not dependent on heparan sulphate proteoglycans, implying that an unknown sialic acid-independent entry receptor for BKPyV exists.

microbiology↗

bioRxiv2021

A ganglioside-based senescence-associated immune checkpoint

Senescent cells accumulate in aging tissues, and their elimination can favor healthy aging1-4. Therefore, therapeutic interventions targeting cellular senescence may be promising strategies for delaying or reversing a vast range of age-related diseases5. As cells of the immune system are responsible for senescent cell elimination6-11, a possible anti-aging and pro-healthspan treatment is the specific activation of the immune system to induce senescent cell clearance. However, whether this elimination is limited by an immune checkpoint leading to tolerance of senescence cells is currently unknown. Here, we show that cellular senescence, elicited by various stressors other than oncogenic activation, triggers immune escape toward natural killer (NK) cells, which may thus limit the use of anti-senescence immunotherapies. Moreover, using mass spectrometry, we reveal that senescent cells reshuffle their glycosphingosine composition, toward a marked increase in the ganglioside content, including the appearance of disialylated ganglioside GD3. This senescence associated GD3 overexpression results from transcriptional upregulation of the gene encoding the enzyme ST8SIA1, which is responsible for GD3 synthesis. The high level of GD3 leads to a strong immunosuppressive signal affecting NK cell-mediated immunosurveillance. In a mouse model of lung fibrosis, senescent cell-dependent NK cell immunosuppression is blunted by in vivo administration of anti-GD3 monoclonal antibodies leading to a clear anti-fibrotic effect. These results demonstrate that GD3 upregulation in senescent cells drives a switch from immune clearance toward immune tolerance of senescent cells. Therefore, we propose that GD3 level acts as a senescence-associated immune checkpoint (SIC) that regulates NK cell functions toward senescent cells. Thus, targeting GD3 with specific antibodies may be a promising strategy for the development of effective anti-senescence immunotherapies.

immunology↗