CD8⁺ T-cells of CLL-bearing mice acquire a transcriptional program of T-cell activation and exhaustion

Chronic lymphocytic leukemia (CLL) is associated with an accumulation of oligoclonal CD8⁺ effector T-cells, which control leukemia progression in mice, but gradually acquire a dysfunctional phenotype along with disease progression. Exhaustion of CD8⁺ T-cells is characterized by increased expression of inhibitory receptors like PD-1, decreased proliferation, and reduced effector function such as cytokine production, which reduces anti-tumor control. Despite the accumulation of exhausted PD-1⁺ CD8⁺ T-cells in secondary lymphoid organs of CLL patients, immune checkpoint blockade as a means to reinvigorate anti-tumor T-cell activity has not shown the expected efficacy. This highlights the need for a better understanding of T-cell exhaustion in CLL. Here, we uncover the transcriptional program of T-cell exhaustion in CLL by comparing naïve with dysfunctional effector CD8⁺ T-cells with high PD-1 expression from mice after adoptive transfer of Eµ-TCL1 leukemic cells. Our data provide clear evidence for activation-induced dysfunction of CD8⁺ T-cells in the CLL microenvironment and assess the heterogeneity in the expression of functionally relevant proteins in specific clusters of CD8⁺ T-cells at a single-cell level.