Toll-like Receptor-9 Agonist Reverses T Cell Exhaustion in a Murine Model of Pediatric B-ALL

Despite significant treatment advances, the poor long-term prognosis for children with relapsed/refractory B-cell acute lymphoblastic leukemia (B-ALL) persists. The application of immune cell-based therapies, such as chimeric antigen receptor-expressing T cells and bispecific T-cell engagers, has improved progression-free survival for many B-ALL patients. However, the majority of these patients still experience disease relapse. An improved understanding of the mechanisms that impair T cell function in B-ALL patients could inform strategies to further improve outcomes. Recent studies have revealed T cell exhaustion, especially as indicated by PD-1 and Tim- 3 expression, to be predictive of disease relapse and overall survival in B-ALL. However, the precise contribution of T cell dysfunction to B-ALL development remains unclear. In this study, we explore the biology that leads to impaired T cell function and investigate potential approaches to restore it using both transgene-driven and syngeneic leukemia cell transplant models of B-ALL. First, we used the Emu-Ret transgenic mouse model of hyperdiploid B-ALL to investigate the induction of exhaustion-associated marker expression (PD-1, CTLA-4 and Tim-3) on CD4 and CD8 T cells. Longitudinal analysis of marker expression in various settings revealed that an upregulation of PD-1 and Tim-3, but not CTLA-4, on T cells occurred only in the presence of leukemia cells, not during the extended, nascent preleukemia phase. This suggests that T cell exhaustion occurs exclusively during the established malignancy phase, highlighting the dynamic nature of T cell responses as disease progresses. Next, B-ALL cells from moribund Emu-Ret mice were transplanted into 4-6-week-old wild type BALB/c mice and markers of T cell exhaustion were measured as disease progressed. Expression of PD-1 and Tim-3 on T cells correlated with disease progression. Notably, a significant increase in these markers was already detectable at low leukemia burden. These results indicate that T cell exhaustion is not simply a reflection of high disease burden and confirm the differing abilities of preleukemic and leukemic cells to affect T cell phenotype. Previously, we have demonstrated the ability of toll-like receptor (TLR) ligands to induce immune control over B-ALL cells. Thus, we investigated the impact of CpG oligodeoxynucleotides (CpG ODN), a ligand for TLR-9, on B-ALL depletion and T cell dysfunction. The treatment of leukemia bearing mice with CpG ODN led to a decrease in PD-1 and Tim-3 expression on T cells, which was also associated with a reduction in leukemia burden. We are currently investigating the functional implications of these expression changes using in vitro assays of T cell proliferation, cytokine production, and cytotoxicity. Additionally, we are also assessing if anti-tumour control by T cells can be revived in vivo, by comparing B-ALL progression and mouse survival after administration of antibodies against exhaustion markers, with or without CpG ODNs as adjuvant therapy. Overall, this study reveals that the functional impact of interactions between B-ALL cells and the immune system evolves during leukemia development. These insights could inform therapeutic strategies to overcome B-ALL immune evasion mechanisms and enhance patient outcomes.

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