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Increased PVR Expression on Bone Marrow Macrophages May Promote Resistance to TIGIT Blockade in Multiple Myeloma
Ester Lozano1,2,3, Mari-Pau Mena2,3, Glòria Garrabou4,5
1Department of Cell Biology, Physiology and Immunology, School of Biology, University of Barcelona (UB), Barcelona, Spain.
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.
Insights
In multiple myeloma, poliovirus receptor (PVR) expression on bone marrow macrophages inhibits T-cell responses, causing resistance to TIGIT blockade therapy.
Area of Science:
- Immunology
- Oncology
- Cell Biology
Background:
- TIGIT blockade therapy shows variable efficacy in multiple myeloma.
- Investigating resistance mechanisms to TIGIT blockade is crucial for improving treatment outcomes.
Purpose of the Study:
- To investigate if increased TIGIT ligand expression contributes to resistance against TIGIT blockade in multiple myeloma.
- To understand the role of bone marrow macrophages and their ligands in T-cell mediated anti-myeloma immunity.
Main Methods:
- Multiparameter flow cytometry to characterize bone marrow macrophages.
- Ex vivo experiments assessing TIGIT ligand effects on plasma cell survival.
- NanoString technology and real-time PCR for gene expression analysis.
Main Results:
- Multiple myeloma patients exhibited decreased bone marrow macrophage frequency and altered immunophenotype.
- Polio virus receptor (PVR) and nectin-2 supported malignant plasma cell survival.
- PVR, but not nectin-2, diminished the efficacy of TIGIT blockade and IL2 therapy.
- IL2 increased TIGIT on T cells and PVR on macrophages, leading to reduced cytotoxic T cells.
Conclusions:
- Interleukin-2 (IL2) induces TIGIT on T cells, while increased PVR expression inhibits cytotoxic T cells.
- This PVR-mediated inhibition promotes plasma cell survival and resistance to TIGIT blockade in multiple myeloma.
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