Annotation-Free Prediction of Cancer Cells and Glands and Spatial Analysis of Immune Cells

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Abstract Prostate cancer is classified as “immune-cold” due to limited infiltration of immune cells and no clear correlation between immune cells and clinical outcomes. However, immune cells are found in prostate cancers and the spatial relationships between these immune cells and cancer cells/glands have not been investigated, partly due to a lack of automated tools that classify both cancerous cells/glands. In this paper, we have developed an end-to-end tool (TOPAZ: T issue O rganization identification using s PA tial proteomics) that combines multiplexed single-cell protein data with histology images to: 1) predict cancerous versus non-cancerous epithelial cells using a Gaussian-mixture model; 2) predict cancerous/non-cancerous gland type using a principal curve estimation. Using TOPAZ to assign cancer and non-cancerous labels to cells and glands, we extracted multiscale spatial features from the classification results—including immune dense-region geometrical features and cell-to-gland distances— and correlated the features with risk of biochemical recurrence and cancer grade. Tissue-microarrays containing 753 cores from 217 prostate cancer patients underwent multiplexed immunofluorescent imaging (Cell DIVE, Leica) for epithelial cell markers (panCK26, S6, NaKATPase), basal cell markers (p63, CK5), a cancer cell marker (AMACR), and T cell markers (CD3, CD4, CD8, FOXP3, CD68). Cancerous/non-cancerous cell classification from TOPAZ achieved 82% sensitivity and 99% specificity against expert annotation, and the pipeline further predicted cancerous/non-cancerous glands without manual threshold tuning. Regulatory-T-cell and helper-T-cell percentages decreased, and macrophage percentage increased with grade increase (P < 0.05). When the median distance from cancerous gland centroids to the nearest regulatory or helper T-cell exceeded approximately 50 µm, the hazard of biochemical recurrence doubled (log-rank P < 0.01). The open-source Shiny app TOPAZ ( https://chunglab.bmi.osumc.edu/TOPAZ ) packages the workflow, predicting individual cell types and gland shapes. By combining probabilistic cell typing with gland-shape modeling, TOPAZ yields interpretable multiscale spatial features linked to prognosis and is released as an open web app for unrestricted use. Author Summary Spatial distribution of cancerous cells/glands and immune cell distribution has not been considered as a prognosticator in prostate cancer. In addition, automated tools that can quantify and integrate these distributions are lacking. We combined high-dimensional single-cell protein measurements with histology images to map gland structure in prostate cancer tissue. Our web-based tool, TOPAZ ( https://chunglab.bmi.osumc.edu/TOPAZ ) predicts whether each epithelial cell and gland in virtual H&E image is cancerous or not. Once the predictions are made, a spatial analysis workflow helps quantify spatial features of immune cells relative to the glands and correlate with recurrence risk and grades. Across 753 tissue cores from 217 prostate cancer patients, helper and regulatory-T-cells located more than about 50 µm away from cancerous epithelial glands were associated with a higher risk of biochemical recurrence. The pipeline provides new insights for researchers and pathologists into prostate cancer progression and biochemical recurrence through integration of spatial location of cancer glands and immune cells.

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