Asymmetric induction of IL-23R by CpG and IL-15 in proliferative CLL fractions highlights intraclonal heterogeneity in chronic lymphocytic leukemia

Chronic lymphocytic leukemia (CLL) is sustained by complex interactions with the microenvironment, which provides signals for leukemic cell survival and proliferation. Among these, cytokines of the IL-12 family have emerged as relevant regulators of immune responses and tumor biology, yet their contribution to CLL remains incompletely defined. Previous studies showed that CLL cells can acquire responsiveness to IL-23 after T cell–dependent stimulation with CD40L, raising the question of whether T cell–independent signals can similarly induce functional receptor expression.

Here we investigated the effect of CpG oligodeoxynucleotides, alone or in combination with interleukin-15 (IL-15), on IL-12 family receptor expression in CLL cells. We found that CpG + IL-15 stimulation significantly increased IL-23R and IL-12Rβ1 expression, while IL-12Rβ2 remained largely unresponsive. As a consequence, the complete IL-23 receptor complex was robustly induced, whereas IL-12 receptor assembly was only marginally enhanced. This skewing toward IL-23 rather than IL-12 signaling suggests that innate immune stimuli preferentially promote pathways supporting inflammation and survival, while limiting tumor-suppressive IL-12 responsiveness.

Analysis of intraclonal heterogeneity revealed an asymmetric distribution of IL-23R among CXCR4/CD5-defined subfractions: the proliferative fraction, representing recently divided cells, expressed higher levels of IL-23R compared to the resting fraction. These findings suggest that IL-23 responsiveness is particularly enriched in the proliferating compartment of the leukemic clone.

Overall, our results indicate that CpG and IL-15 stimulation drive a selective expansion of IL-23 signaling capacity in CLL, with preferential engagement of proliferative subfractions. This imbalance between IL-23 activation and insufficient IL-12Rβ2 induction may represent a critical pathogenic mechanism and a potential therapeutic target.