Abstract
Thymocyte selection-associated high-mobility group box (TOX) is a DNA-binding factor that is able to regulate transcription by modifying local chromatin structure and modulating the formation of multi-protein complexes. TOX has multiple roles in the development of the adaptive immune system including development of CD4 T cells, NK cells and lymph node organogenesis. However very few antibodies recognizing this molecule have been reported and no extensive study of the expression of TOX in reactive and neoplastic lymphoid tissue has been performed to date. In the present study, we have investigated TOX expression in normal and neoplastic lymphoid tissues using a novel rat monoclonal antibody that recognizes its target molecule in paraffin-embedded tissue sections. A large series of normal tissues and B- and T-cell lymphomas was studied, using whole sections and tissue microarrays. We found that the majority of precursor B/T lymphoblastic, follicular and diffuse large B-cell lymphomas, nodular lymphocyte-predominant Hodgkin lymphomas and angioimmunoblastic T-cell lymphomas strongly expressed the TOX protein. Burkitt and mantle cell lymphomas showed TOX expression in a small percentage of cases. TOX was not found in the majority of chronic lymphocytic leukemia, myelomas, marginal zone lymphomas and classical Hodgkin lymphomas. In conclusion, we describe for the first time the expression of TOX in normal and neoplastic lymphoid tissues. The co-expression of TOX and PD-1 identified in normal and neoplastic T cells is consistent with recent studies identifying TOX as a critical regulator of T-cell exhaustion and a potential immunotherapy target. Its differential expression may be of diagnostic relevance in the differential diagnosis of follicular lymphoma, the identification of the phenotype of diffuse large B-cell lymphoma and the recognition of peripheral T-cell lymphoma with a follicular helper T phenotype.
Highlights
Thymocyte selection-associated high-mobility group box (TOX) is a member of a small subfamily of proteins (TOX2, TOX3 and TOX4) that share almost identical High Mobility Group (HMG)-box sequences and are highly conserved between mice and humans [1]
Gene expression data from lymph nodes with follicular lymphomas (FL), lymph nodes with nodal marginal zone lymphomas (NMZL), spleens infiltrated by chronic lymphocytic leukemia (CLL), lymph nodes infiltrated by extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue (MALT), lymph nodes infiltrated by splenic marginal zone lymphoma (SMZL), spleen infiltrated by mantle cell lymphoma (MCL) and reactive lymphoid tissue (8 lymph nodes and 7 spleens) were available from previous studies [14, 20]
TOX gene expression in FL was further analyzed in comparison to other B-cell lymphomas (MALT, SMZL, MCL and CLL) and reactive lymphoid tissue, where we found significant TOX overexpression in FL for all tests
Summary
Thymocyte selection-associated high-mobility group box (TOX) is a member of a small subfamily of proteins (TOX2, TOX3 and TOX4) that share almost identical High Mobility Group (HMG)-box sequences and are highly conserved between mice and humans [1]. Forced expression of Tox in the thymus of transgenic mice changed the differentiation program of developing T cells, suggesting its involvement as a key player in differentiation during lymphocyte development [4]. Six studies have identified TOX as critical transcriptional and epigenetic coordinator of CD8+ T-cell exhaustion in response to T-cell receptor stimulation and NFAT activation in infection and cancer [8,9,10,11,12,13]. These studies identify TOX as a central player in the regulation of T-cell responses and a future immunotherapeutic target
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