Manipulating the TCR signaling network for cellular immunotherapy: Challenges & opportunities

•T cell receptor signaling plays a key role in T cell activation and differentiation processes.•Recent studies examine the effects of specific molecular networks downstream of T cell receptor signaling.•Targeting T cell receptor signaling may provide novel cancer immunotherapeutic approaches with decreased adverse side effects. T cells can help confer protective immunity by eliminating infections and tumors or drive immunopathology by damaging host cells. Both outcomes require a series of steps from the activation of naïve T cells to their clonal expansion, differentiation and migration to tissue sites. In addition to specific recognition of the antigen via the T cell receptor (TCR), multiple accessory signals from costimulatory molecules, cytokines and metabolites also influence each step along the progression of the T cell response. Current efforts to modify effector T cell function in many clinical contexts focus on the latter – which encompass antigen-independent and broad, contextual regulators. Not surprisingly, such approaches are often accompanied by adverse events, as they also affect T cells not relevant to the specific treatment. In contrast, fine tuning T cell responses by precisely targeting antigen-specific TCR signals has the potential to radically alter therapeutic strategies in a focused manner. Development of such approaches, however, requires a better understanding of functioning of the TCR and the biochemical signaling network coupled to it. In this article, we review some of the recent advances which highlight important roles of TCR signals throughout the activation and differentiation of T cells during an immune response. We discuss how, an appreciation of specific signaling modalities and variant ligands that influence the function of the TCR has the potential to influence design principles for the next generation of pharmacologic and cellular therapies, especially in the context of tumor immunotherapies involving adoptive cell transfers.