Immune checkpoints in thymic epithelial tumors: challenges and opportunities

Thymic malignancies are rare mediastinal cancers, classified according to the World Health Organization's histopathologic classification which distinguishes thymomas from thymic carcinomas. One key consideration when discussing immunotherapy for thymic epithelial tumors is that one-third of patients diagnosed with thymomas present at the time of diagnosis with autoimmune disorders, the most common being myasthenia gravis. The first step in the understanding of autoimmunity in thymic epithelial tumors is to distinguish true autoimmune disorders from paraneoplastic syndromes; besides pathophysiology, clinical correlates, impact on oncological management and survival may differ strongly. Autoimmune disorders are related to a deregulation in the physiological role of the thymus (i.e. to induce central tolerance to tissue self-antigens) through control of differentiation and subsequent positive and negative selection of immature T cells; from a clinical standpoint, in thymomas, once autoimmune disorders are present, they may not regress significantly after thymectomy. PD-L1 expression, while observed in more than 90% of epithelial cells of the normal thymus with a medullar tropism respecting Hassall's corpuscles, has also been identified in thymomas and thymic carcinomas using various immunohistochemistry protocols. Immune checkpoint inhibitors of the PD-1/PD-L1 axis have been assessed in advanced and metastatic thymic epithelial tumors, mainly thymic carcinomas. Several case reports have been published, and four trials have assessed the efficacy and safety of these inhibitors. Immunotherapy is not standard given the frequent occurrence of severe autoimmune disorders, and clinical trials are ongoing.