Lymphoma endothelium preferentially expresses Tim-3 and facilitates the progression of lymphoma by mediating immune evasion

Abstract

Angiogenesis is increasingly recognized as an important prognosticator associated with the progression of lymphoma and as an attractive target for novel modalities. We report a previously unrecognized mechanism by which lymphoma endothelium facilitates the growth and dissemination of lymphoma by interacting with circulated T cells and suppresses the activation of CD4+ T cells. Global gene expression profiles of microdissected endothelium from lymphoma and reactive lymph nodes revealed that T cell immunoglobulin and mucin domain–containing molecule 3 (Tim-3) was preferentially expressed in lymphoma-derived endothelial cells (ECs). Clinically, the level of Tim-3 in B cell lymphoma endothelium was closely correlated to both dissemination and poor prognosis. In vitro, Tim-3+ ECs modulated T cell response to lymphoma surrogate antigens by suppressing activation of CD4+ T lymphocytes through the activation of the interleukin-6–STAT3 pathway, inhibiting Th1 polarization, and providing protective immunity. In a lymphoma mouse model, Tim-3–expressing ECs promoted the onset, growth, and dissemination of lymphoma by inhibiting activation of CD4+ T cells and Th1 polarization. Our findings strongly argue that the lymphoma endothelium is not only a vessel system but also a functional barrier facilitating the establishment of lymphoma immune tolerance. These findings highlight a novel molecular mechanism that is a potential target for enhancing the efficacy of tumor immunotherapy and controlling metastatic diseases.

Dysregulation of TIM-3–Galectin-9 Pathway in the Cystic Fibrosis Airways

“…TIM-3 has been shown to be a negative modulator of Th-1 type immune response (32,64). This dual effect of TIM-3/galectin-9 on different cell types has previously been reported in dendritic cells (21) and endothelial cell (27) versus T cells. However, in a chronic inflammatory scenario, as observed in the CF lung, dysregulation of TIM-3 signaling may have a detrimental effect.…”

“…There is mounting evidence that TIM-3 is a potent regulator of both the adaptive and innate immune responses; however, the mechanism depends on both cell type and specific disease. Indeed, TIM-3 has exhibited modulatory properties involved in tumor cell proliferation and immune evasion in nonimmune cells including endothelial cells (27,28) and epidermal melanocytes (29). TIM-3 function has also been implicated in neutrophil recruitment and tissue injury in several in vivo models (30)(31)(32).…”

The inhibition of the T-cell immunoglobulin and mucin domain 3 (Tim3) pathway enhances the efficacy of tumor vaccine

“…Nasopharyngeal tumors secrete exosomes containing galectin-9, which have been implicated in immune escape by the tumor through the induction of tumor-specific Tim3 + T-cell death [22]. Furthermore, Tim3 expressed in lymphoma-associated endothelium leads to tumor progression through the inhibition of CD4 + T-cell activation and Th1 polarization [23]. In addition, the interaction of Tim3 expressed by endothelial cells with melanoma cells facilitates metastasis through the activation of NF-kB in the melanoma cells [24].…”

Prognostic Value of T Cell Immunoglobulin Mucin-3 in Prostate Cancer

“…the activation of the interleukin-6-STAT3 pathway and also facilitates the establishment of lymphoma immune tolerance (Huang et al, 2010). However, the role of TIM-3 in prostate cancer remains largely unknown.…”