Biology subjects

Degos, C.

Publications and source records attributed to Degos, C..

2 recordsLinked to original sources

bioRxiv2023

Tertiary lymphoid structures are associated with enhanced macrophage and dendritic cell activation and proximity to CD8+ T cells, which better predict the clinical outcome of cervical cancer patients

BackgroundCervical tumors are usually treated using surgery, chemotherapy, and radiotherapy, and would benefit from immunotherapies. However, the immune microenvironment in cervical cancer remains poorly described. Tertiary lymphoid structures (TLS) were recently described as markers for better immunotherapy response and overall better prognosis in cancer patients. MethodsWe integratedly evaluated the cervical tumor immune microenvironment, and specifically TLS importance, using combined high-throughput phenotyping, soluble factor dosage, spatial interaction analyses, and statistical analyses. ResultsWe demonstrate that TLS presence is associated with a more inflammatory soluble microenvironment, with the presence of B cells as well as more activated macrophages and dendritic cells (DCs). Furthermore, this myeloid cell activation is associated with expression of immune checkpoints, such as PD-L1 and CD40, and close proximity of activated conventional DC2 to CD8+ T cells, therefore indicating better immune interactions and tumor control. Finally, we associate TLS presence, greater B cell density, and activated DC density to improved progression-free survival, and present it as an additional prognostic marker. ConclusionTo conclude, our results provide an exhaustive depiction of the cervical tumor immune microenvironment where TLS presence marks cell activation and immunotherapy target expression. These findings provide predictive clues for patient response to targeted immunotherapies. SignificanceTLS maturation stratifies cervical cancer patients and associates with improved prognosis. TLS associate with the expression of immune checkpoints, notably in the macrophage compartment, which may represent a new therapeutic strategy.

immunology↗

bioRxiv2022

Anti-HVEM mAb therapy improves antitumoral immunity both in vitro and in vivo, in a novel transgenic mouse model expressing human HVEM and BTLA molecules challenged with HVEM expressing tumors

BackgroundTNFRF-14/HVEM is the ligand for BTLA and CD160 negative immune co-signaling molecules as well as viral proteins. Its expression is dysregulated with an overexpression in tumors and a connection with tumors of adverse prognosis. MethodsWe developed C57BL/6 mouse models co-expressing human huBTLA and huHVEM as well as antagonistic monoclonal antibodies (mAbs) that completely prevent the interactions of HVEM with its ligands. ResultsHere, we show that the anti-HVEM18-10 mAb increases primary human {beta}-T cells activity alone (CIS-activity) or in the presence of HVEM-expressing lung or colorectal cancer cells in vitro (TRANS-activity). Anti-HVEM18-10 synergizes with anti-PD-L1 mAb to activate T cells in the presence of PDL-1 positive tumors, but is sufficient to trigger T cell activation in the presence of PD-L1 negative cells. In order to better understand HVEM18-10 effect in vivo and especially disentangle its CIS and TRANS effects, we developed a knock-in (KI) mouse model expressing human BTLA (huBTLA+/+) and a KI mouse model expressing both human BTLA and human HVEM (huBTLA+/+ /huHVEM+/+ (DKI)). In vivo pre-clinical experiments performed in both mouse models showed that HVEM18-10 treatment was efficient to decrease human HVEM+ tumor growth. In the DKI model, anti-HVEM 18-10 treatment induces a decrease of exhausted CD8+ T cells and regulatory T cells and an increase of Effector memory CD4+ T cells within the tumor. Interestingly, mice which completely rejected tumors ({+/-} 20%) did not develop tumors upon re-challenge in both settings, therefore showing a marked T cell-memory phenotype effect. ConclusionsAltogether, our preclinical models validate anti-HVEM18-10 as a promising therapeutic antibody to use in clinics as a monotherapy or in combination with existing immunotherapies (anti-PD1/anti-PDL-1/anti-CTLA-4).

immunology↗