Investigation of immune repertoires in thymoma.

Abstract

e21117 Background: Paraneoplastic autoimmune manifestations are seen in 30 to 40% of thymoma cases. Thymus plays the main role in T- cell maturation with ‘negative selection’ of autoreactive T-cells. Due to reasons not well understood, this function is deranged in thymomas resulting in dysregulation of immune function, loss of ‘self-tolerance’ and autoreactivity. The low cost and high-throughput of next generation sequencing techniques now make it feasible to analyze extensive T-cell receptor(TCR) gene rearrangements in peripheral blood lymphocytes. Methods: 40 patients with thymoma were identified between December, 2010 and September, 2019 at Indiana University. Whole blood samples were collected after diagnosis of thymoma but prior to thymectomy. 20 patients developed paraneoplastic manifestations at some point during the disease course. Genomic DNA was isolated from whole blood samples and TCR analysis performed using a commercially available next generation sequencing assay. This was compared with the control population of 20 patients who did not demonstrate any paraneoplastic features during their disease course. Patients were matched based on age, clinical stage and WHO classification. Results: Paraneoplastic manifestations seen in the 20 patients included Myasthenia Gravis (n = 12), Good’s Syndrome (n = 2), immune mediated cytopenia (n = 3) including pure red cell aplasia, pure white cell aplasia and thrombocytopenia, neurologic manifestations such as encephalitis (n = 2), Autoimmune Autonomic Neuronopathy(n = 1) and Isaac’s Syndrome (n = 2). Some patients also demonstrated more than one paraneoplastic syndrome. The onset and course of these manifestations varied; onset prior to diagnosis of thymoma, onset after thymectomy and improving or worsening clinical features after thymectomy. Since the exact mechanism of autoimmunity is still unknown, we attempted to detect differences in TCR subsets between these two groups. Our study shows that it is technically feasible to interrogate the peripheral blood lymphocytes of thymoma patients for TCR gene clonality and diversity. Conclusions: Diverse autoimmune syndromes can be described in thymoma patients with varying clinical course and severity. Although our study is underpowered, TCR gene sequencing is efficient and may not only improve our understanding of these paraneoplastic syndromes but also identify biomarkers for their diagnosis. Our research could also potentially lead to development of targeted treatment options in the future based on TCR manipulation.