Sequential Single-Cell Transcriptional and Protein Marker Profiling Reveals TIGIT as a Marker of CD19 CAR-T Cell Dysfunction in Patients with Non-Hodgkin Lymphoma

Zachary Jackson, Changjin Hong, Robert Schauner, Boro Dropulic, Paolo F. Caimi, Marcos de Lima, Maria Florencia Giraudo, Kalpana Gupta, Jane S. Reese, Tae Hyun Hwang, David N. Wald

Research output: Contribution to journalArticlepeer-review

5 Scopus citations

Abstract

Chimeric antigen receptor T-cell (CAR-T cell) therapy directed at CD19 produces durable remissions in the treatment of relapsed/refractory non-Hodgkin lymphoma (NHL). Nonetheless, many patients receiving CD19 CAR-T cells fail to respond for unknown reasons. To reveal changes in 4-1BB–based CD19 CAR-T cells and identify biomarkers of response, we used singlecell RNA sequencing and protein surface marker profiling of patient CAR-T cells pre-and postinfusion into patients with NHL. At the transcriptional and protein levels, we note the evolution of CAR-T cells toward a nonproliferative, highly differentiated, and exhausted state, with an enriched exhaustion profile in CAR-T cells of patients with poor response marked by TIGIT expression. Utilizing in vitro and in vivo studies, we demonstrate that TIGIT blockade alone improves the antitumor function of CAR-T cells. Altogether, we provide evidence of CAR-T cell dysfunction marked by TIGIT expression driving a poor response in patients with NHL. SIGNIFICANCE: This is the first study investigating the mechanisms linked to CAR-T patient responses based on the sequential analysis of manufactured and infused CAR-T cells using single-cell RNA and protein expression data. Furthermore, our findings are the first to demonstrate an improvement of CAR-T cell efficacy with TIGIT inhibition alone.

Original languageEnglish (US)
Pages (from-to)1886-1903
Number of pages18
JournalCancer discovery
Volume12
Issue number8
DOIs
StatePublished - Aug 1 2022
Externally publishedYes

ASJC Scopus subject areas

  • Oncology

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