Modulating T Cell Responses by Targeting CD3

SIMPLE SUMMARY: CD3 complex provides the first signal sensed by the TCR of the lymphocyte to trigger its activation. Thus, it becomes a very attractive receptor to determine the fate of the immune response in different contexts from tolerance induction to immune activation. We discuss CD3-TCR complex assembly and the current and emerging approaches to harvest CD3 activity for immunotherapy. ABSTRACT: Harnessing the immune system to fight cancer has become a reality with the clinical success of immune-checkpoint blockade (ICB) antibodies against PD(L)-1 and CTLA-4. However, not all cancer patients respond to ICB. Thus, there is a need to modulate the immune system through alternative strategies for improving clinical responses to ICB. The CD3-T cell receptor (TCR) is the canonical receptor complex on T cells. It provides the “first signal” that initiates T cell activation and determines the specificity of the immune response. The TCR confers the binding specificity whilst the CD3 subunits facilitate signal transduction necessary for T cell activation. While the mechanisms through which antigen sensing and signal transduction occur in the CD3–TCR complex are still under debate, recent revelations regarding the intricate 3D structure of the CD3–TCR complex might open the possibility of modulating its activity by designing targeted drugs and tools, including aptamers. In this review, we summarize the basis of CD3–TCR complex assembly and survey the clinical and preclinical therapeutic tools available to modulate CD3–TCR function for potentiating cancer immunotherapy.