Multidimensional single-cell analysis identifies a role for CD2-CD58 interactions in clinical antitumor T cell responses
Gabrielle Romain, … , Sattva S. Neelapu, Navin Varadarajan
Gabrielle Romain, … , Sattva S. Neelapu, Navin Varadarajan
Published July 26, 2022
Citation Information: J Clin Invest. 2022;132(17):e159402. https://doi.org/10.1172/JCI159402.
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Research Article Immunology Oncology

Multidimensional single-cell analysis identifies a role for CD2-CD58 interactions in clinical antitumor T cell responses

Abstract

The in vivo persistence of adoptively transferred T cells is predictive of antitumor response. Identifying functional properties of infused T cells that lead to in vivo persistence and tumor eradication has remained elusive. We profiled CD19-specific chimeric antigen receptor (CAR) T cells as the infusion products used to treat large B cell lymphomas using high-throughput single-cell technologies based on time-lapse imaging microscopy in nanowell grids (TIMING), which integrates killing, cytokine secretion, and transcriptional profiling. Our results show that the directional migration of CD19-specific CAR T cells is correlated with multifunctionality. We showed that CD2 on T cells is associated with directional migration and that the interaction between CD2 on T cells and CD58 on lymphoma cells accelerates killing and serial killing. Consistent with this, we observed that elevated CD58 expression on pretreatment tumor samples in patients with relapsed or refractory large B cell lymphomas treated with CD19-specific CAR T cell therapy was associated with complete clinical response and survival. These results highlight the importance of studying dynamic T cell–tumor cell interactions in identifying optimal antitumor responses.

Authors

Gabrielle Romain, Paolo Strati, Ali Rezvan, Mohsen Fathi, Irfan N. Bandey, Jay R T. Adolacion, Darren Heeke, Ivan Liadi, Mario L. Marques-Piubelli, Luisa M. Solis, Ankit Mahendra, Francisco Vega, Laurence J.N. Cooper, Harjeet Singh, Mike Mattie, Adrian Bot, Sattva S. Neelapu, Navin Varadarajan

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Figure 3

CD58 expression on DLBCL cells enables multifunctionality of CAR T cells.

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CD58 expression on DLBCL cells enables multifunctionality of CAR T cells...
(A) The DLBCL cell line HBL-1 is deficient in CD58 expression due to homozygous deletion of the CD58 loci. The long form of CD58 was lentivirally transduced into HBL-1 cell lines. (B) Flow cytometric assays demonstrating the relative expression of CD19 and CD58 on HBL-1 and HBL-1–CD58+ cell lines. (C) Design of the CAR constructs and CD2 expression in 19-28z and 19-41BBz CAR T cells. (D) T cell–mediated killing of HBL-1 and HBL-1–CD58+ cells evaluated using TIMING (E:T 1:1–2). For each group, data were derived from a minimum of 150 single CAR T cells. P values were computed using 2-tailed Fisher’s exact test. Representative micrographs illustrating monokilling of HBL-1 cells and serial killing of HBL-1-CD58+ cells are shown. Time is displayed as hours and minutes. Scale bar: 20 μm. (E) Kinetic differences in the nature of interaction between CAR T cells and HBL-1 and HBL-1–CD58+ cells evaluated using TIMING (E:T 1:1). For each group, data were derived from a minimum of 150 individual CAR T cells. P values were computed using Mann-Whitney U test. Representative micrographs illustrating the duration of contact before killing between a 19-28z T cell and HBL-1 cell, and a 19-28z T cell and HBL-1–CD58+ cell. Time is displayed as hours and minutes. Scale bars: 20 μm. Black bars represent the median, and dotted lines denote quartiles.