TCR Pathway Mutations in Mature T Cell Lymphomas

Mature T cell lymphomas are heterogeneous neoplasms that are aggressive and resistant to treatment. Many of these cancers retain immunological properties of their cell of origin. They express cytokines, cytotoxic enzymes, and cell surface ligands normally induced by TCR signaling in untransformed T cells. Until recently, their molecular mechanisms were unclear. Recently, high-dimensional studies have transformed our understanding of their cellular and genetic characteristics. Somatic mutations in the TCR signaling pathway drive lymphomagenesis by disrupting autoinhibitory domains, increasing affinity to ligands, and/or inducing TCR-independent signaling. Collectively, most of these mutations augment signaling pathways downstream of the TCR. Emerging data suggest that these mutations not only drive proliferation but also determine lymphoma immunophenotypes. For example, RHOA mutations are sufficient to induce disease-relevant CD4+ T follicular helper cell phenotypes. In this review, we describe how mutations in the TCR signaling pathway elucidate lymphoma pathophysiology but also provide insights into broader T cell biology.