Matriptase as a Novel Therapeutic Target in Non-Hodgkin Lymphoma

Abstract

Non-Hodgkin Lymphoma (NHL) is a heterogeneous group of cancers derived from lymphocytes that is increasing in incidence. Advances in genetic diagnostic techniques and the introduction of immunotherapy have allowed significant progress in the treatment of NHL. However, NHL that relapses having become treatment refractory after a promising initial response, accounts for approximately one-third of all cases, and remains a serious cause of morbidity and mortality. There are urgent needs for new drug targets and biomarkers of drug resistance for NHL. The type II transmembrane serine protease matriptase could be a novel candidate for clinical application to NHL due to its ectopic expression on the cell surface of NHL and lack of expression in normal B-lymphocytes. In addition, matriptase exhibits a high degree of proteolytic activity in this disease, as the result of an imbalanced matriptase: HAI-1 expression in aggressive NHLs, which has been shown to promote proliferation and invasiveness of these cancer cells.

Coexpression of HAI-1 is, however, typically thought of being essential for matriptase synthesis and intracellular trafficking by suppressing the adverse impact resulted from the undesired and harmful matriptase premature zymogen activation in the secretory pathway. The mechanism by which NHL cells are able to express matriptase on the cell surface in the absence of HAI-1 coexpression, remains a largely unexplored question and results in unregulated extracellular matriptase proteolytic activity to promote B-cell malignancy. In this thesis, I began with the identification of HAI-2 as the primary regulator of matriptase enzymatic activity. Characterization of the impact of HAI-2 expression on matriptase regulation further reveals that HAI-2 paradoxically increases matriptase proteolytic activity, which subsequently contributes to the proliferation of neoplastic B-cells and reduced sensitivity to Ibrutinib, the first line drug for some NHL and leukemias.

HAI-2 resembles HAI-1 in many aspects, including being a potent and specific catalytic inhibitor of matriptase and its ability to facilitate matriptase synthesis and trafficking en route to the plasma membrane. In contrast to the cell surface localization of HAI-1, the primary intracellular localization of HAI-2 limits its access to extracellular active matriptase. Therefore, the co-expression of HAI-2 in neoplastic B-cells paradoxically enhances matriptase enzymatic activity. This dysregulated matriptase activity confers upon neoplastic B-cells the ability to activate ERK phosphorylation, which is associated with increased proliferation and relative resistance to Ibrutinib. Suppression of matriptase expression and/or zymogen activation via reduced matriptase expression or reduced HAI-2 expression or suppressed matriptase zymogen activation by the matriptase-specific mAb verified the roles of matriptase enzymatic activity in ERK phosphorylation, cell proliferation and reduced Ibrutinib sensitivity. The unusual relationship, by which HAI-2 is required for and promotes matriptase enzymatic activity and subsequently the pro-malignant activity of matriptase, is further manifested by the worst disease outcome observed in the NHL patients with high matriptase and high HAI-2 expression, compared to NHL patients with other expression combinations between matriptase and HAI-2. In summary, dysregulated pericellular matriptase proteolysis medicated by co-expression of HAI-2 contributes to various malignant aspects of neoplastic B-cells and could have the potential to be developed into a biomarker to identify and a drug target to circumvent the resistance to the current treatments in NHL patients.