Mapping the evolution of T cell states during response and resistance to adoptive cellular therapy
Pavan Bachireddy, Elham Azizi, Cassandra Burdziak, Vinhkhang N. Nguyen, Christina Ennis, Katie Maurer, Cameron Y. Park, Zi-Ning Choo, Shuqiang Li, Satyen H. Gohil, Neil Ruthen, Zhongqi Ge, Derin B. Keskin, Nicoletta Cieri, Kenneth J. Livak, Haesook T. Kim, Donna Neuberg, Robert J. Soiffer, Jerome Ritz, Edwin P. Alyea, Dana Pe’er, Catherine J. Wu
Abstract
To elucidate mechanisms by which T cells eliminate leukemia, we study donor lymphocyte infusion (DLI), an established immunotherapy for relapsed leukemia. We model T cell dynamics by integrating longitudinal, multimodal data from 94,517 bone marrow-derived single T cell transcriptomes in addition to chromatin accessibility and single T cell receptor sequencing from patients undergoing DLI. We find that responsive tumors are defined by enrichment of late-differentiated T cells before DLI and rapid, durable expansion of early differentiated T cells after treatment, highly similar to "terminal" and "precursor" exhausted subsets, respectively. Resistance, in contrast, is defined by heterogeneous T cell dysfunction. Surprisingly, early differentiated T cells in responders mainly originate from pre-existing and novel clonotypes recruited to the leukemic microenvironment, rather than the infusion. Our work provides a paradigm for analyzing longitudinal single-cell profiling of scenarios beyond adoptive cell therapy and introduces Symphony, a Bayesian approach to infer regulatory circuitry underlying T cell subsets, with broad relevance to exhaustion antagonists across cancers.