Divergent macrophage-regulated T cell states determine response to Bacillus Calmette-Guérin vaccine in high-risk bladder cancer.

BACKGROUNDPrimary therapy for high-risk bladder cancer (BCa) is repeated instillations of the tuberculosis vaccine Bacillus Calmette-Guérin (BCG). Although BCG reduces the risk of recurrence by more than half, the mechanisms underlying its immune-activating effects remain unknown. Our objective was to investigate how the immune response differs between BCG responders and nonresponders and to compare systemic and local immune responses.METHODSWe performed scRNA-seq of isolated immune cells adjacent to high-risk bladders in BCG responders and nonresponders before and after BCG. We also compared concurrent scRNA-seq profiles of circulating immune cell populations with those of bladder immune cells.RESULTSWe observed an increase in Th17-like Th1 cells in BCG responders, characterized by greater expression of proinflammatory cytokines. By contrast, nonresponders showed increased CD8+ T cell exhaustion and Treg cells. We found that the primary mechanism driving divergent T cell activity is altered polarization and immunosuppressive signaling with myeloid cells. Using a machine learning-based approach, we identified that Th17-like Th1 cytokines, such as IL-17, IL-21, and IL-26, are predictive of response, which was subsequently validated in a separate BCG-treated BCa cohort.CONCLUSIONTogether, these findings suggest that dynamic regulation of myeloid-T cell interactions can be critical for outcomes of BCG-treated BCa.FUNDINGBX005599 and BX003692 (Veterans Health Administration), HT94252410507 (Department of Defense), R01CA298333 (National Cancer Institute), and Robert H. Lurie Comprehensive Cancer Center H Foundation Core Facility Pilot Project Award.