Tumor microenvironments impair T cell receptor affinity and function

CD8+ T cells underpin effective anti-tumor immune responses in melanoma; however, their functions are attenuated due to various immunosuppressive factors in the tumor microenvironment (TME), resulting in disease progression. T cell function is elicited by the T cell receptor (TCR), which recognizes antigen peptide-major histocompatibility complex (pMHC) expressed on tumor cells via direct physical contact, i.e., two-dimensional (2D) interaction. TCR–pMHC 2D affinity plays a central role in antigen recognition and discrimination, and is sensitive to both the conditions of the T cell and the microenvironment in which it resides. Herein, we demonstrate that CD8+ T cells residing in TME have lower 2D TCR–pMHC bimolecular affinity and TCR–pMHC–CD8 trimolecular avidity, pull fewer TCR–pMHC bonds by endogenous forces, flux lower level of intracellular calcium in response to antigen stimulation, exhibit impaired in vivo activation, and show diminished anti-tumor effector function. These detrimental effects are localized in the tumor and tumor draining lymph node (TdLN), and affect both antigen-inexperienced and antigen-experienced CD8+ T cells irrespective of their TCR specificities. These findings implicate impaired antigen recognition as a mechanism of T cell dysfunction in the TME. ### Competing Interest Statement The authors have declared no competing interest.