Abstract
In general, there is a lack of good immunotherapy targets within the spectrum of haematological malignancies. However haematopoietic stem cell transplants and continuing antigen discovery have allowed further insight into how further improvements in outcomes for patients might be achieved. Most patients with haematological malignancies can be treated with conventional therapies such as radio- and chemotherapy and will attain first remission. However the removal of residual diseased cells is essential to prevent relapse and its associated high mortality. PASD1 is one of the most tissue restricted cancer-testis (CT) antigens with expression limited to primary spermatagonia in healthy tissue. However, characterisation of PASD1 expression in cancers has been predominantly focussed on haematological malignancies where the inappropriate expression of PASD1 was first identified. PASD1 has one of the highest frequencies of expression of all CT antigens in acute myeloid leukaemia, with some suggestion of its role as a biomarker in diffuse large B-cell lymphoma. Here we describe the characterisation of the function and expression patterns of PASD1 in cell lines and primary tissues. Development of DNA vaccines targeting PASD1 epitopes demonstrate effective ex vivo T-cell responses in terms of IFNγ secretion and tumour cell killing. Of particular note these vaccines have led to the destruction of cells which process and present endogenous PASD1 indicating that effectively primed CTLs could kill PASD1-positive tumour cells.
Highlights
The quest to identify novel antigens has been the focus of a number of studies over the last four decades [1,2]
To maximise the chance of finding new CT antigens cDNA libraries made from healthy testis cDNA have been immunoscreened with patient sera
KM-H2, established from the pleural effusion of a patient with Hodgkin’s disease of mixed cellular type [46] and the mantle cell lymphoma (MCL)-derived cell line Granta519 showed nuclear staining with PASD1-1 and PASD1-2 antibodies while strong cytoplasmic labelling with PASD1-2 was observed in a subpopulation of Granta519 cells
Summary
The quest to identify novel antigens has been the focus of a number of studies over the last four decades [1,2]. In 1995 Sahin et al described the use of the serological identification of antigens by recombinant expression cloning (SEREX) to discover antigens in a range of cancer tissues [7,8] In this technique patient immunoglobulins (IgG) from peripheral blood sera were used to immunoscreen cDNA from tumours, cell lines or normal testis tissues in the form of polypeptides on the surface of the phage. To maximise the chance of finding new CT antigens cDNA libraries made from healthy testis cDNA have been immunoscreened with patient sera This has led to the identification of a number of CT antigens including cTAGE-1, NY-ESO-1, SSX2 [13,14] and PASD1 [15,16]. KH-M2 established from the pleural effusion of a patient with Hodgkin's disease of mixed cellular type KMS-12-BM MM cell line
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