Abstract
The capacity of T cells to recognize and mount an immune response against tumor antigens depends on the large diversity of the T-cell receptor (TCR) repertoire generated in the thymus during the process of T-cell development. However, this process is dramatically impaired by immunological insults, such as that caused by cytoreductive cancer therapies and infections, and by the physiological decline of thymic function with age. Defective thymic function and a skewed TCR repertoire can have significant clinical consequences. The presence of an adequate pool of T cells capable of recognizing specific tumor antigens is a prerequisite for the success of cancer immunotherapy using checkpoint blockade therapy. However, while this approach has improved the chances of survival of patients with different types of cancer, a large proportion of them do not respond. The limited response rate to checkpoint blockade therapy may be linked to a suboptimal TCR repertoire in cancer patients prior to therapy. Here, we focus on the role of the thymus in shaping the T-cell pool in health and disease, discuss how the TCR repertoire influences patients’ response to checkpoint blockade therapy and highlight approaches able to manipulate thymic function to enhance anti-tumor immunity.
Highlights
Optimal immunological response to a large array of unknown antigens requires the presence of a diverse T-cell receptors (TCRs) repertoire, which represents the primary determinant for the likelihood of recognizing specific antigens [1]
T-cell immunity is critical to control cancer occurrence and relapse; a more diverse TCR repertoire increases the likelihood of tumor-antigen recognition and mounting an effective immune response
A more diverse TCR repertoire increases the likelihood of tumor-antigen recognition and of mounting an effective immune response
Summary
Optimal immunological response to a large array of unknown antigens requires the presence of a diverse T-cell receptors (TCRs) repertoire, which represents the primary determinant for the likelihood of recognizing specific antigens [1]. The reduction in thymic functionality and in the TCR diversity impaired immune surveillance and may provide a supportive environment for tumors to elude T-cell-mediated response. T-cell immunity is critical to control cancer occurrence and relapse; a more diverse TCR repertoire increases the likelihood of tumor-antigen recognition and mounting an effective immune response.
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