Multiple Myeloma (MM) is the second most frequent hematologic malignancy in adults in the Western world. The bone marrow microenvironment plays a critical role in MM progression by supporting malignant plasma cell (PC) survival, immune evasion, and proliferation. Among immune checkpoints, TIGIT has recently emerged as a relevant immunoregulatory molecule, capable of dampening cytotoxic responses and enhancing immune suppression. We investigated the expression of TIGIT in the bone marrow of newly diagnosed MM patients and its correlation with disease characteristics and microenvironmental features. We enrolled 25 consecutive patients with newly diagnosed MM. Bone marrow samples were collected for cytomorphology, cytogenetics (FISH), and immunohistochemistry using the Cytomatrix system. TIGIT expression was analyzed in bone marrow-infiltrating immune cells. Histological evaluation and confocal microscopy assessed immune cell localization, neutrophil extracellular trap (NET) formation, and proinflammatory cytokine expression. Clinical parameters, staging (ISS, R-ISS, R2-ISS), cytogenetic risk, and laboratory values were correlated with TIGIT status. TIGIT was expressed in 86% (19/22) of evaluable samples. TIGIT-positive patients had a significantly higher frequency of advanced R-ISS stages (p = 0.01), high-risk cytogenetics (100%), and elevated LDH (> 220 mU/ml, 100% TIGIT+). Among patients with PC% >60% or FLC ratio > 100, 92% were TIGIT+. Morphological differences were evident between groups: TIGIT-negative PCs were larger and altered, while TIGIT-positive PCs showed polarized nuclei and proximity to neutrophils. TIGIT-positive samples displayed increased neutrophils undergoing NETosis, as confirmed by neutrophil elastase and Ly6b co-expression (p = 0.0067). Elevated IL-6 (p = 0.0003) and IL-8 (p = 0.004) in TIGIT-positive samples suggest a proinflammatory microenvironment promoting neutrophil recruitment and NETosis. TIGIT expression in the bone marrow of MM patients is associated with more aggressive disease features and an inflammatory microenvironment enriched with NET-forming neutrophils. These findings support TIGIT as a potential biomarker of disease severity and a therapeutic target in MM
PROINFLAMMATORY BONE MARROW NICHES AND NEUTROPHIL ACTIVATION ARE ASSOCIATED WITH TIGIT EXPRESSION IN MULTIPLE MYELOMA
Francesca Arciprete;Antonella Bianchi;Luigi Rigacci;Anna Crescenzi;Maria Zingariello
Conceptualization
;
2025-01-01
Abstract
Multiple Myeloma (MM) is the second most frequent hematologic malignancy in adults in the Western world. The bone marrow microenvironment plays a critical role in MM progression by supporting malignant plasma cell (PC) survival, immune evasion, and proliferation. Among immune checkpoints, TIGIT has recently emerged as a relevant immunoregulatory molecule, capable of dampening cytotoxic responses and enhancing immune suppression. We investigated the expression of TIGIT in the bone marrow of newly diagnosed MM patients and its correlation with disease characteristics and microenvironmental features. We enrolled 25 consecutive patients with newly diagnosed MM. Bone marrow samples were collected for cytomorphology, cytogenetics (FISH), and immunohistochemistry using the Cytomatrix system. TIGIT expression was analyzed in bone marrow-infiltrating immune cells. Histological evaluation and confocal microscopy assessed immune cell localization, neutrophil extracellular trap (NET) formation, and proinflammatory cytokine expression. Clinical parameters, staging (ISS, R-ISS, R2-ISS), cytogenetic risk, and laboratory values were correlated with TIGIT status. TIGIT was expressed in 86% (19/22) of evaluable samples. TIGIT-positive patients had a significantly higher frequency of advanced R-ISS stages (p = 0.01), high-risk cytogenetics (100%), and elevated LDH (> 220 mU/ml, 100% TIGIT+). Among patients with PC% >60% or FLC ratio > 100, 92% were TIGIT+. Morphological differences were evident between groups: TIGIT-negative PCs were larger and altered, while TIGIT-positive PCs showed polarized nuclei and proximity to neutrophils. TIGIT-positive samples displayed increased neutrophils undergoing NETosis, as confirmed by neutrophil elastase and Ly6b co-expression (p = 0.0067). Elevated IL-6 (p = 0.0003) and IL-8 (p = 0.004) in TIGIT-positive samples suggest a proinflammatory microenvironment promoting neutrophil recruitment and NETosis. TIGIT expression in the bone marrow of MM patients is associated with more aggressive disease features and an inflammatory microenvironment enriched with NET-forming neutrophils. These findings support TIGIT as a potential biomarker of disease severity and a therapeutic target in MMI documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
