Ibrutinib sensitizes CLL cells to venetoclax by interrupting TLR9-induced CD40 upregulation and protein translation

Chronic lymphocytic leukemia (CLL) cells upregulate Bcl-2 proteins within the lymph node (LN) microenvironment. Signaling via B-cell receptor, Toll-like receptors and CD40 collectively reduce sensitivity to the BCL-2 inhibitor venetoclax. Time-limited treatment with venetoclax plus the BTK-inhibitor ibrutinib results in deep remissions, but how this combination affects LN-related signaling is not yet completely clear. Therefore, samples obtained from the HOVON141/VISION phase 2 clinical trial were used to analyze this. Two cycles of lead-in ibrutinib monotherapy resulted in decreased protein expression of Bcl-2 proteins in circulating CLL cells. Strikingly, at this timepoint CD40-induced venetoclax resistance was strongly attenuated, as was expression of CD40. Since CD40 signaling occurs within the CLL LN, we tested various LN-related signals that could affect CD40 signaling. While BCR stimulation had only a minor effect, TLR9 stimulation via CpG led to significantly increased CD40 expression and importantly, reverted the effects of ibrutinib treatment on venetoclax sensitivity by inducing overall protein translation. Together, these findings identify a novel effect of ibrutinib: interruption of TLR9-induced CD40 upregulation and translation of pro-survival proteins. This mechanism may potentially further inhibit priming of CLL cells in the LN microenvironment for venetoclax resistance.

Automated summary

Chronic lymphocytic leukemia (CLL) cells upregulate Bcl-2 proteins in the lymph node (LN) microenvironment, reducing sensitivity to the BCL-2 inhibitor venetoclax through signaling pathways involving B-cell receptor, Toll-like receptors, and CD40. A study analyzing samples from the HOVON141/VISION clinical trial found that two cycles of lead-in ibrutinib treatment decreased Bcl-2 protein expression and attenuated CD40-induced venetoclax resistance. Additionally, TLR9 stimulation reversed the effects of ibrutinib on venetoclax sensitivity by increasing CD40 expression and protein translation. These findings suggest that ibrutinib interrupts TLR9-induced CD40 upregulation, potentially inhibiting CLL cell priming for venetoclax resistance in the LN microenvironment.