A T-cell repertoire timestamp is at the core of responsiveness to CTLA-4 blockade

The reasons for clinical success and failure involved with blocking the receptor CTLA-4 are still largely unknown. It has been shown that the biology of the response to anti CTLA-4 involves the dynamics of specific T-cell clones. Here, we quantified the dynamics of these clones, the T cell receptor repertoire, throughout four weeks of treatment with anti CTLA-4. Repertoire sequencing of mice treated with anti CTLA-4 shows an initial increase in clonality in tandem with a decrease in diversity, both in the short term. These effects gradually subside. Analysis of the repertoire shows that the response to treatment is tightly connected to the shared and public parts of the T-cell repertoire. We were further able to distinguish time dependent behavior of specific TCR sequences and cell types. Finally, we performed motif analysis of our data. Most importantly, our analysis suggests that a single time point might be used to inform the physician of the true response to treatment. The identification of such singular time point within the course of treatment highlights the importance of temporal analyses of the immune response. The results strengthen the hypothesis that treatment with anti CTLA-4 results in a wax and wane effect on the TCR repertoire, and that measurements of its time-dependent behavior are essential for effective treatment.