Development of a model system to characterize antigen-specific T cell receptors based on TCR affinity and T cell function

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2021

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Xia, Amanda

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Abstract

Modern T cell cancer immunotherapies are based on the ability of cytotoxic T cells to recognize and attack infected cells. This process is activated by the T cell receptor (TCR) recognizing a peptide-bound major histocompatibility complex (pMHC) on the surface of target cells. It is of particular interest to target neoantigens, antigens derived from tumor-specific DNA mutations, to create a tumor-specific immune response. One method of broadening the T cell response is to genetically engineer the patient’s T cells to express neoantigen-specific TCRs isolated from healthy donors. It is important to understand how the affinity of the TCR-pMHC interaction relates to T cell function in the context of T cells expressing foreign TCR. Here, I created a model system to study human TCRs specific for cytomegalovirus (CMV) pp65, a commonly recognized CMV antigen. By transducing primary T cells with pp65-specific TCRs of known TCR affinity, I investigated how differences in TCR affinity related to T cell function. My model system demonstrated that transduced T cells could maintain high TCR expression over a sustained period and that the affinity of the TCR expressed positively correlated with cytokine production. This sets the foundation of a promising approach to study neoantigen-specific TCRs for the development of melanoma immunotherapy.

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