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

By Guangxu Jin, Gang Xue, Rui-Sheng Wang, Ling-Yun Wu, Lance Miller, Yong Lu, Wei Zhang

Posted 02 Nov 2018
bioRxiv DOI: 10.1101/459867

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 inactivated effector and cytotoxic signatures; and 'D low' specific to responders, alternatively enriched with T cell activation and cytolytic effector T cell signatures. We also observed a large portion of 'D negative' bystander T cells irrelevant to response. Notably, D-low TILs in clinical responders display very low LAG3 expression. To reverse the functionality of the LAG3-high TILs after receiving αPD-1+αCTLA-4, we combined αLAG3 with αPD-1+αCTLA-4 in treating a murine tumor model. Remarkably, αLAG3+αPD-1+αCTLA-4 displays extraordinary antitumor efficacy to eradicate advanced tumors, which is associated with burst GZMB-hi TIL populations; whereas αPD-1+αCTLA-4 or αPD-1+αCTLA-4 plus other ICBs as control only induce moderate tumor growth inhibition. Our study has important implications for cancer immunotherapy as providing both accurate predictions of ICB response and alternative strategy to reverse ICB resistance.

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