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 3

Opposing Th17 and Treg signatures define response to BCG.

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Opposing Th17 and Treg signatures define response to BCG. (A) UMAP plot ...
(A) UMAP plot of CD4+ T cells from the blood and bladder tissue of BCG-naive, -responsive, and -unresponsive groups. (B) Dot plot of representative genes expressed in each major cluster. Dot size represents percentage of cells expressing the gene; color represents scaled expression of the gene. (C) Proportion of CD4+ cell subsets in blood and bladder, measured by Welch’s t test. Left: Box-and-whisker plots showing the distribution of immune cell type proportions for each patient. Right: Stacked bar plots summarizing immune cell type proportions after downsampling to 100 cells per sample. (D) Proportion of CD4+ cell subsets in the bladder tissue of BCG-naive, -responsive, and -unresponsive groups, measured by Welch’s t test. Left: Box-and-whisker plots showing the distribution of CD4+ cell subset proportions. Right: Stacked bar plots summarizing CD4+ cell subset proportions after downsampling to 100 cells per sample. (E) Heatmap showing differentially expressed genes of CD4+ T cell subsets in BCG-naive (N), -responsive (R), and -unresponsive (U) groups. (F) Slingshot trajectory plot showing predicted cellular differentiation possibilities of CD4+ T cells. (G) Linear regression between a patient’s proportion of Th17-like and Treg cells. Each point represents 1 patient. Gray shaded region, 95% CI. Box-and-whisker plots depict median, IQR, and whiskers extending to 1.5× IQR in C and D. *P < 0.05, ****P < 0.0001.