hDirect-MAP: projection-free single-cell modeling of response to checkpoint immunotherapy.

Abstract

There is a lack of robust generalizable predictive biomarkers of response to immune checkpoint blockade in multiple types of cancer. We develop hDirect-MAP, an algorithm that maps T cells into a shared high-dimensional (HD) expression space of diverse T cell functional signatures in which cells group by the common T cell phenotypes rather than dimensional reduced features or a distorted view of these features. Using projection-free single-cell modeling, hDirect-MAP first removed a large group of cells that did not contribute to response and then clearly distinguished T cells into response-specific subpopulations that were defined by critical T cell functional markers of strong differential expression patterns. We found that these grouped cells cannot be distinguished by dimensional-reduction algorithms but are blended by diluted expression patterns. Moreover, these identified response-specific T cell subpopulations enabled a generalizable prediction by their HD metrics. Tested using five single-cell RNA-seq or mass cytometry datasets from basal cell carcinoma, squamous cell carcinoma and melanoma, hDirect-MAP demonstrated common response-specific T cell phenotypes that defined a generalizable and accurate predictive biomarker.

• Authors: Yong Lu, Gang Xue, Ningbo Zheng, Kun Han, Wenzhong Yang, Rui-Sheng Wang, Lingyun Wu, Lance D Miller, Timothy Pardee, Pierre L Triozzi, Hui-Wen Lo, Kounosuke Watabe, Stephen T C Wong, Boris C Pasche, Wei Zhang, Guangxu Jin
• Journal: Briefings in bioinformatics (Brief Bioinform) Vol. 23 Issue 2 (03 10 2022) ISSN: 1477-4054 [Electronic] England
• PMID: 35037026 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: © The Author(s) 2022. Published by Oxford University Press. All rights reserved. For Permissions, please email: [email protected].

Chemical References

• Biomarkers

Topics

• Biomarkers
• Humans
• Immunotherapy
• Melanoma (drug therapy, genetics)
• T-Lymphocytes