GPNMB: exploring a novel target for therapy in Hodgkin lymphoma

Masand, Navta (2021). GPNMB: exploring a novel target for therapy in Hodgkin lymphoma. University of Birmingham. Ph.D.

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Abstract

Glycoprotein non-metastatic melanoma protein B (GPNMB) is a transmembrane protein highly expressed in multiple tumours, including classical Hodgkin lymphoma (cHL); a tumour in which the malignant Hodgkin and Reed-Sternberg (HRS) cells rely on the tumour microenvironment (TME) to survive and evade detection by the host immune system. In this study, I explore the contribution of GPNMB to immune evasion of cHL as a novel therapeutic target.

I have shown that GPNMB is highly expressed in tumour-associated macrophages (TAM) in cHL tissues but expression is highly variable. In vitro differentiation of macrophages (from CD14\(^+\) monocytes) was shown to be associated with an increase in GPNMB expression, including the generation of a soluble form of GPNMB (sGPNMB). sGPNMB partially inhibited T-cell activation and T-cell recognition of Epstein-Barr virus (EBV)-specific epitopes in cHL cell lines. Preliminary experiments indicated that the inhibition of T cell activation by GPNMB could be overcome with GPNMB neutralising antibodies.

This work provides evidence in support of the hypothesis that GPNMB can mediate an immune checkpoint that inhibits anti-tumour cytotoxic T-lymphocytes (CTL). It provides a basis for further investigations designed to explore the therapeutic potential of targeting GPNMB in cHL.

Type of Work:

Thesis (Doctorates > Ph.D.)

Award Type:

Doctorates > Ph.D.

Supervisor(s):