Divergent macrophage-regulated T cell states determine response to Bacillus Calmette-Guérin vaccine in high-risk bladder cancer
Ryan J. Brown, Mairah T. Khan, Andrew J. Houston, Hongshen Niu, Joseph R. Podojil, Bonnie Choy, Weiguo Cui, Joshua J. Meeks
Ryan J. Brown, Mairah T. Khan, Andrew J. Houston, Hongshen Niu, Joseph R. Podojil, Bonnie Choy, Weiguo Cui, Joshua J. Meeks
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Clinical Research and Public Health Immunology Oncology

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

Abstract

BACKGROUND Primary 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.METHODS We 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.RESULTS We 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.CONCLUSION Together, these findings suggest that dynamic regulation of myeloid–T cell interactions can be critical for outcomes of BCG-treated BCa.FUNDING BX005599 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.

Authors

Ryan J. Brown, Mairah T. Khan, Andrew J. Houston, Hongshen Niu, Joseph R. Podojil, Bonnie Choy, Weiguo Cui, Joshua J. Meeks

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Figure 1

Study design and patient cohort for immune profiling of the BCa tumor microenvironment during BCG therapy.

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Study design and patient cohort for immune profiling of the BCa tumor mi...
(A) Sample collection from patients with BCa. For most patients, whole and bladder biopsies adjacent to the tumor were collected prospectively with CD45+ isolation and analyzed by scRNA-seq using the BD Rhapsody system. (B) Patients were prospectively enrolled at 2 distinct time points: before (BCG naive) and after BCG therapy. After BCG therapy, patients were classified as either responsive or resistant, depending on the result of the bladder biopsy. (C) Metadata of each patient’s covariates were sequenced, including sex, age, tumor stage, tissue compartments, and the patient’s BCG response CIS, carcinoma in situ.