Same-Slide Spatial Multi-Omics Integration Reveals Tumor Virus-Linked Spatial Reorganization of the Tumor Microenvironment

Yeo, Y. Y.; Chang, Y.; Qiu, H.; Yiu, S. P. T.; Michel, H. A.; Wu, W.; Jin, X.; Kure, S.; Parmelee, L.; Luo, S.; Cramer, P.; Lee, J. L.; Wang, Y.; Yeung, J.; Ahmar, N. E.; Simsek, B.; Mohanna, R.; Orden, M. V.; Lu, W.; Livak, K. J.; Li, S.; Shahryari, J.; Kingsley, L.; Al-Humadi, R. N.; Nasr, S.; Nkosi, D.; Sadigh, S.; Rock, P.; Frauenfeld, L.; Kaufmann, L.; Zhu, B.; Basak, A.; Dhanikonda, N.; Chan, C. N.; Krull, J.; Cho, Y. W.; Chen, C.-Y.; Lee, J. Y. J.; Wang, H.; Zhao, B.; Loo, L.-H.; Kim, D. M.; Schurch, C. M.; Shalek, A. K.; Boussiotis, V.; Zhang, B.; Howitt, B.; Signoretti, S.; Hodi, F. S

doi:10.1101/2024.12.20.629650

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bioRxiv · 10.1101/2024.12.20.629650

Same-Slide Spatial Multi-Omics Integration Reveals Tumor Virus-Linked Spatial Reorganization of the Tumor Microenvironment

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Abstract

The advent of spatial transcriptomics and spatial proteomics have enabled profound insights into tissue organization to provide systems-level understanding of diseases. Both technologies currently remain largely independent, and emerging same slide spatial multi-omics approaches are generally limited in plex, spatial resolution, and analytical approaches. We introduce IN-situ DEtailed Phenotyping To High-resolution transcriptomics (IN-DEPTH), a streamlined and resource-effective approach compatible with various spatial platforms. This iterative approach first entails single-cell spatial proteomics and rapid analysis to guide subsequent spatial transcriptomics capture on the same slide without loss in RNA signal. To enable multi-modal insights not possible with current approaches, we introduce k-bandlimited Spectral Graph Cross-Correlation (SGCC) for integrative spatial multi-omics analysis. Application of IN-DEPTH and SGCC on lymphoid tissues demonstrated precise single-cell phenotyping and cell-type specific transcriptome capture, and accurately resolved the local and global transcriptome changes associated with the cellular organization of germinal centers. We then implemented IN-DEPTH and SGCC to dissect the tumor microenvironment (TME) of Epstein-Barr Virus (EBV)-positive and EBV-negative diffuse large B-cell lymphoma (DLBCL). Our results identified a key tumor-macrophage-CD4 T-cell immunomodulatory axis differently regulated between EBV-positive and EBV-negative DLBCL, and its central role in coordinating immune dysfunction and suppression. IN-DEPTH enables scalable, resource-efficient, and comprehensive spatial multi-omics dissection of tissues to advance clinically relevant discoveries.

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Yeo, Y. Y., Chang, Y., Qiu, H., Yiu, S. P. T., Michel, H. A., Wu, W., Jin, X., Kure, S., Parmelee, L., Luo, S., Cramer, P., Lee, J. L., Wang, Y., Yeung, J., Ahmar, N. E., Simsek, B., Mohanna, R., Orden, M. V., Lu, W., Livak, K. J., Li, S., Shahryari, J., Kingsley, L., Al-Humadi, R. N., Nasr, S., Nkosi, D., Sadigh, S., Rock, P., Frauenfeld, L., Kaufmann, L., Zhu, B., Basak, A., Dhanikonda, N., Chan, C. N., Krull, J., Cho, Y. W., Chen, C.-Y., Lee, J. Y. J., Wang, H., Zhao, B., Loo, L.-H., Kim, D. M., Schurch, C. M., Shalek, A. K., Boussiotis, V., Zhang, B., Howitt, B., Signoretti, S., Hodi, F. S. 2024-12-22. Same-Slide Spatial Multi-Omics Integration Reveals Tumor Virus-Linked Spatial Reorganization of the Tumor Microenvironment. https://doi.org/10.1101/2024.12.20.629650

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