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 IL12 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 IL23 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 (IL15), on IL12 family receptor expression in CLL cells. We found that CpG + IL15 stimulation significantly increased IL23R and IL12Rbeta1 expression, while IL12Rbeta2 remained largely unresponsive. As a consequence, the complete IL23 receptor complex was robustly induced, whereas IL12 receptor assembly was only marginally enhanced. This skewing toward IL23 rather than IL12 signaling suggests that innate immune stimuli preferentially promote pathways supporting inflammation and survival, while limiting tumor-suppressive IL12 responsiveness. Analysis of intraclonal heterogeneity revealed an asymmetric distribution of IL23R among CXCR4/CD5 defined subfractions: the proliferative fraction, representing recently divided cells, expressed higher levels of IL23R compared to the resting fraction. These findings suggest that IL23 responsiveness is particularly enriched in the proliferating compartment of the leukemic clone. Overall, our results indicate that CpG and IL15 stimulation drive a selective expansion of IL23 signaling capacity in CLL, with preferential engagement of proliferative subfractions. This imbalance between IL23 activation and insufficient IL12Rbeta2 induction may represent a critical pathogenic mechanism and a potential therapeutic target.