SPP1+ Neutrophils Mediate Resistance to Immune Checkpoint Blockade in BAP1-Inactivated Tumors.

Abstract

BAP1 inactivation, observed across multiple human cancers, is linked to immune checkpoint blockade (ICB) resistance and adverse clinical outcomes. The mechanisms underlying BAP1-associated ICB sensitivity could provide potential targets to enhance ICB efficacy. In this study, we showed that BAP1 inactivation fosters an immunosuppressive tumor microenvironment, marked by increased infiltration of M2-like macrophages and neutrophils. Single-cell transcriptomic analysis revealed an expansion of SPP1+ neutrophils in ICB-treated, BAP1-inactivated tumors. These SPP1+ neutrophils displayed a protumorigenic phenotype and conferred resistance to anti-PD-1 therapy by engaging with cytotoxic T cells via PD-1/PD-L1 signaling. Notably, depletion of neutrophils, but not macrophages, restored sensitivity to ICB in BAP1-inactivated tumors. Mechanistically, BAP1 loss significantly increased C-C motif chemokine ligand 2 (CCL2) secretion, driving neutrophil SPP1+ polarization, delaying neutrophil apoptosis, and promoting ICB resistance. This resistance could be significantly mitigated by targeting the CCL2-C-C chemokine receptor type 2 (CCR2) axis. These results underscore the role of BAP1 in modulating the immune landscape and suggest that targeting CCL2-CCR2-mediated neutrophil polarization may overcome ICB resistance in BAP1-inactivated tumors. BAP1 inactivation induces immunotherapy resistance and engenders an immunosuppressive microenvironment by enhancing CCL2 secretion and SPP1+ neutrophil polarization, which can be circumvented with CCL2-CCR2 inhibition to restore immune checkpoint blockade sensitivity.