Table 1.

Summary of the ways the CAR-T cell targets influence CAR signaling

Approaches	Influence
Length of antigen protrusion from target membrane	Long targets reduce the efficacy of immunological synapse formation and other functions when CAR has a longer spacer/hinge, e.g., proper degranulation. In contrast, short target molecules require a longer spacer/hinge region in order to reach the antigen-binding site.
Antigen density	The antigen density determines the activation level of the CAR-T cells. CAR-T cells respond to target cells when the antigen density expressed exceeds a threshold level. CAR-T cells can be designed to recognize cancer cells expressing higher amount of antigens instead of the relatively low amount of antigen expressed by normal cells.
Original function	Different antigens distinctly affect CAR-T signaling due to their original properties. For example, pMHC as the target antigen may affect CAR-T cell signaling by recruiting coreceptors. An affinity threshold for CAR also exists for pMHC, where high affinity CARs lose the ability to recognize a target pMHC with specificity.