Cancer Mutations Targeting TNFRSF14 alter Microenvironment Checkpoint Interactions to Limit Tumor Clearance by Cytotoxic Cells

The roles of many non-oncogenic mutations in cancer may influence tumor growth, survival, or how tumors interact with their surroundings. Here we characterize the functional relevance of missense mutations within the gene encoding the tumor necrosis receptor family member HVEM ( TNFRSF14 ), a locus frequently targeted within human lymphoma and other cancers. We find that point mutations identified in human lymphoma were localized to the extracellular domain and specifically target ligand binding, resulting in preferential loss of CD160 and BTLA interactions compared to LIGHT ( TNFSF14 ). Missense mutations were associated with alterations in cytotoxic effector cell signatures within tumor biopsies, while deletion mutations were associated with changes in myeloid cell signatures. Finally, we find that mutated HVEM proteins retained the capacity to inhibit T cell signaling through BTLA, while reducing costimulation of cytolysis in NK cells through CD160. Together, these data provide evidence for how immune selective pressures may drive mutation of TNFRSF14 resulting in greater tumor fitness.