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Circulating Clonally Expanded T Cells Reflect Functions of Tumor Infiltrating T Cells

By Liliana Lucca, Pierre-Paul Axisa, Benjamin Lu, Brian Harnett, Shlomit Jessel, Le Zhang, Khadir Raddassi, Lin Zhang, Kelly Olino, James Clune, Meromit Singer, Harriet M. Kluger, David A. Hafler

Posted 02 Oct 2020
bioRxiv DOI: 10.1101/2020.09.30.321240

Understanding the relationship between tumor and peripheral immune environments could allow longitudinal immune monitoring in cancer. Here, we examined whether T cells that share the same TCRαβ and are found in both tumor and blood can be interrogated to gain insight into the ongoing tumor T cell response. Paired transcriptome and TCRαβ repertoire of circulating and tumor-infiltrating T cells were analyzed from matched tumor and blood from patients with metastatic melanoma at the single cell level. We found that in circulating T cells matching clonally expanded tumor-infiltrating T cells (circulating TILs), gene signatures of effector functions, but not terminal exhaustion, reflect those observed in the tumor. In contrast, features of exhaustion are displayed predominantly by T cells present only in tumor. Finally, genes associated with a high degree of blood-tumor TCR sharing were overexpressed in tumor tissue after immunotherapy. These data demonstrate that circulating TILs, identified by TCRs shared with T cells in tumors, have unique transcriptional expression patterns that may have utility for the interrogation of T cell function in cancer immunotherapy. Summary Combining transcriptomic and TCRαβ repertoire analysis of circulating and tumor-infiltrating CD8 T cells from patients with metastatic melanoma, we identify a blood-based population with effector properties that reflect those of clonally related tumor-resident T cells. ### Competing Interest Statement Though we believe that none of these relationships are conflicts of interest, Dr. Hafler has received research funding from Bristol-Myers Squibb, Sanofi, and Genentech for work unrelated to this project. He has been a consultant over the past ten years for Bristol Myers Squibb, Compass Therapeutics, EMD Serono, Genentech, Juno therapeutics, Novartis Pharmaceuticals, Proclara Biosciences, Sage Therapeutics, and Sanofi Genzyme. Dr. Kluger has received research funding from Bristol-Myers Squibb, Apexigen and Merck. She has been a consultant for Corvus, Biodesix, Roche-Genentech, Pfizer, Iovance, Immunocore, Celldex, Array Biopharma, Merck, Elevate Bio and Instil Bio.

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