Immune checkpoint blockade (ICB) has revolutionized treatment for many solid cancers, yet it remains largely ineffective in hematologic malignancies like chronic lymphocytic leukemia (CLL), where the mechanisms of immune resistance remain poorly understood.
To address this, we used an adoptive CLL transfer model to systematically characterize the CD4⁺ and CD8⁺ T cell landscape in response to CLL and following ICB. Therein, we identified a previously unrecognized population of CLL-responsive regulatory T cells expressing the transcription factor EOMES, which is not observed in other disease contexts such as viral infections or solid tumours, suggesting a disease-specific immunosuppressive program. Mechanistically, EOMES emerged as a central transcriptional regulator shaping both effector and regulatory T cell responses. Specific deletion of EOMES⁺ Tregs significantly enhanced conventional CD4⁺ and CD8⁺ T cell activity, resulting in a rapid reduction of leukemic burden.
With T cells exhibiting features of clonal expansion and functional exhaustion, including high expression of inhibitory receptors such as PD-1, TIM-3 and LAG-3, combinatorial ICB (anti-CTLA-4/anti-PD-L1) acted synergistically to induce profound tumour regression. Unexpectedly, this effect was dependent on CD4+ but not CD8+ T cells, rendering the CD4+ T cell compartment a key target in treating CLL.
Combined, our data not only establish EOMES⁺ Tregs as a critical barrier to effective anti-tumour immunity but also identify CD4+ T cells as major effectors in CLL. These findings uncover a key immunoregulatory circuit in CLL and offer a novel therapeutic angle to enhance ICB efficacy in hematologic malignancies.