BTK Inhibition Reverses MDSC-Mediated Immunosuppression and Enhances Response to Anti-PDL1 Therapy in Neuroblastoma

Simple Summary Neuroblastoma (NB) is the most common pediatric malignancy, and patients with the high-risk disease show a worse prognosis despite advanced treatments, including immunotherapy. Myeloid-derived suppressor cells (MDSC) frequently accumulate in NB tumors, where they induce immunosuppression and hamper efficient antitumor immune responses. In the current study, we observed that Bruton's tyrosine kinase (BTK) is highly expressed in both monocytic and granulocytic MDSCs isolated from spleens of mice bearing NB tumors and administration of BTK inhibitor ibrutinib reduced MDSC-mediated immunosuppression, tumor growth, and enhanced anti-PDL1 checkpoint inhibitor therapy in mice bearing NB tumors. These studies demonstrated that ibrutinib could serve as a promising therapeutic agent to control MDSC-mediated immune suppression in NB. MDSCs are immune cells of myeloid lineage that plays a key role in promoting tumor growth. The expansion of MDSCs in tumor-bearing hosts reduces the efficacy of checkpoint inhibitors and CAR-T therapies, and hence strategies that deplete or block the recruitment of MDSCs have shown benefit in improving responses to immunotherapy in various cancers, including NB. Ibrutinib, an irreversible molecular inhibitor of BTK, has been widely studied in B cell malignancies, and recently, this drug is repurposed for the treatment of solid tumors. Herein we report that BTK is highly expressed in both granulocytic and monocytic murine MDSCs isolated from mice bearing NB tumors, and its increased expression correlates with a poor relapse-free survival probability of NB patients. Moreover, in vitro treatment of murine MDSCs with ibrutinib altered NO production, decreased mRNA expression of Ido, Arg, Tgf beta, and displayed defects in T-cell suppression. Consistent with these findings, in vivo inhibition of BTK with ibrutinib resulted in reduced MDSC-mediated immune suppression, increased CD8+ T cell infiltration, decreased tumor growth, and improved response to anti-PDL1 checkpoint inhibitor therapy in a murine model of NB. These results demonstrate that ibrutinib modulates immunosuppressive functions of MDSC and can be used either alone or in combination with immunotherapy for augmenting antitumor immune responses in NB.

Automated summary

Neuroblastoma (NB) is the most common pediatric malignancy, with high-risk patients showing poor prognosis despite advanced treatments, including immunotherapy. Myeloid-derived suppressor cells (MDSC) play a crucial role in promoting tumor growth and their depletion or blockade has shown benefits in improving responses to immunotherapy in various cancers, including NB. The BTK inhibitor ibrutinib has demonstrated promising results in reducing MDSC-mediated immune suppression, tumor growth, and enhancing response to checkpoint inhibitors in NB, making it a potential therapeutic agent for controlling immune suppression in NB.