Mapping the evolution of Tcell states during response and resistance to adoptive cellular therapy.

Abstract

To elucidate mechanisms by which Tcells eliminate leukemia, we study donor lymphocyte infusion (DLI), an established immunotherapy for relapsed leukemia. We model Tcell dynamics by integrating longitudinal, multimodal data from 94,517 bone marrow-derived single Tcell transcriptomes in addition to chromatin accessibility and single Tcell receptor sequencing from patients undergoing DLI. We find that responsive tumors are defined by enrichment of late-differentiated Tcells before DLI and rapid, durable expansion of early differentiated Tcells after treatment, highly similar to "terminal" and "precursor" exhausted subsets, respectively. Resistance, in contrast, is defined by heterogeneous Tcell dysfunction. Surprisingly, early differentiated Tcells 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 Tcell subsets, with broad relevance to exhaustion antagonists across cancers.