Increased PVR Expression on Bone Marrow Macrophages May Promote Resistance to TIGIT Blockade in Multiple Myeloma. 

Purpose:TIGIT blockade in our ex vivo model of bone marrow (BM) reduced the number of malignant plasma cells (PC) in only half of patients with multiple myeloma. Here, we wanted to investigate whether increased expression of TIGIT ligands may inhibit T-cell immune response promoting resistance to TI...

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Authors: Lozano Garcia, Ester, Mena, Mari-Pau, Garrabou Tornos, Glòria, Cardús, Oriol, Díaz Sánchez, Tania, Moreno Fajardo, David Fernando, Mañé Pujol, Joan, Oliver-Caldés, Aina, Battram, Anthony M., Tovar, Natalia, Cibeira López, M. Teresa, Rodríguez-Lobato, Luis-Gerardo, Bladé, J. (Joan), Fernández de Larrea Rodríguez, Carlos José, Rosiñol Dachs, Laura
Format: article
Status:Versión aceptada para publicación
Publication Date:2024
Country:España
Institution:Universidad de Barcelona
Repository:Dipòsit Digital de la UB
OAI Identifier:oai:diposit.ub.edu:2445/216727
Online Access:https://hdl.handle.net/2445/216727
Access Level:Open access
Keyword:Medul·la òssia
Macròfags
Mieloma múltiple
Bone marrow
Macrophages
Multiple myeloma
Description
Summary:Purpose:TIGIT blockade in our ex vivo model of bone marrow (BM) reduced the number of malignant plasma cells (PC) in only half of patients with multiple myeloma. Here, we wanted to investigate whether increased expression of TIGIT ligands may inhibit T-cell immune response promoting resistance to TIGIT blockade. Experimental Design:We first characterized the number and phenotype of BM macrophages in different stages of the disease by multiparameter flow cytometry. We assessed the effect of TIGIT ligands on PC survival by performing experiments in the ex vivo BM model and analyzed changes in gene expression by using NanoString technology and real-time PCR. Results:The frequency of BM macrophages was significantly decreased in multiple myeloma, which was accompanied by changes in their immunophenotype. Moreover, we found a higher number of malignant PC in ex vivo BM cells cultured onto the poliovirus receptor (PVR) and nectin-2 compared with control, suggesting that both ligands may support PC survival. In addition, the presence of PVR, but not nectin-2, overcame the therapeutic effect of TIGIT blockade or exogenous IL2. Furthermore, exogenous IL2 increased TIGIT expression on both CD4+ and CD8+ T cells and, indirectly, PVR on BM macrophages. Consistently, PVR reduced the number of cytotoxic T cells and promoted a gene signature with reduced effector molecules. Conclusions:IL2 induced TIGIT on T cells in the BM, in which increased PVR expression resulted in cytotoxic T-cell inhibition, promoting PC survival and resistance to TIGIT blockade.

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