DOI: 10.1101/459867Nov 2, 2018Paper

Single-Cell Modeling of CD8+ T Cell Exhaustion Predicts Response to Cancer Immunotherapy

BioRxiv : the Preprint Server for Biology
Guangxu JinWei Zhang


Accurate prediction of response to immune checkpoint blockade (ICB) and simultaneous development of new efficacious ICB strategy are unmet needs for cancer immunotherapy. Despite the advance of existing clinical or computational biomarkers, it is very limited in explicating phenotypic variability of tumor-infiltrating CD8+ T lymphocytes (TILs) at the single-cell level, including tumor-specificity and distinct exhaustion profiles, that are crucial for the responsiveness to ICB. Here we show that a quantitative criterion, D value, for evaluating tumor-specific TIL exhaustion, identified by our new high-dimensional single-cell-based computational method, called HD-scMed, accurately predicts response to the ICB, i.e.,αPD-1, αCTLA-4, and αPD-1+αCTLA-4, with the performance of AUC=100% in human tumors. D-value is the Euclidean distance from a subset of exhausted CD8+ TILs, identified as Pareto Front (PF) by HD-scMed within the high-dimensional expression space of a variety of exhaustion markers, to the baseline TILs excluded by the PF. We phenotypically distinguished two types of TIL 'exhaustion' by the D value, namely 'D Extremely-high' in non-responders, associating with high tumor-specificity imprinted with enhanced exhaustion and...Continue Reading

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