Tumor-specific antigen–reactive tumor-infiltrating lymphocytes can be separated from bystanders.

  • Major Finding: Tumor-specific antigen–reactive tumor-infiltrating lymphocytes can be separated from bystanders.

  • Concept: Using this method, each T-cell type can be more conveniently studied than was previously possible.

  • Impact: This work shows proof-of-concept that a new technique can help characterize immune cells in tumors.

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Tumor-infiltrating lymphocytes (TIL) may be tumor-specific antigen (TSA)–reactive or bystanders, and the presence of TSA-reactive TILs is important for antitumor immunity and response to immunotherapies. With present techniques, detecting which TILs are TSA-reactive and which are bystanders is challenging, so Liu, Li, Chen, and colleagues developed a more convenient method, dubbed FucoID, for making such determinations. In this approach, dendritic cells primed with tumor lysate are modified via chemical attachment of Helicobacter pylori–derived α-(1,3)-fucosyltransferase (FT) to their cell surfaces. FT exhibits high donor substrate tolerance, enabling it to transfer fucose to a variety of proteins found near-ubiquitously in the glycocalyx surrounding cells, including LacNAc and its sialated counterpart. By supplying biotinylated fucose as a substrate, LacNAc on T cells reactive to the TSAs presented by tumor lysate–primed, FT-modified dendritic cells is modified with fucosylated biotin, enabling these T cells to be specifically purified from the larger TIL population using streptavidin. Demonstrating the utility of this approach, tumor-infiltrating TSA-reactive CD4+ and CD8+ T cells along with TSA-suppressive CD4+ T cells were identified. Further, it was established that most TSA-reactive CD8+ T cells expressed PD-1; in contrast, bystander TILs existed in both PD-1+ and PD-1 populations. Further, TSA-reactive TILs had a unique repertoire of T-cell receptors and exhibited a markedly different transcriptomic profile compared with bystander TILs, factors that may influence how TSA-reactive TILs behave in the tumor microenvironment. In summary, this work provides a novel, convenient approach for separating TSA-reactive TILs from other TILs, enabling study of these important antitumor cells, and supplies proof-of-concept evidence of the usefulness of the technique.

Liu Z, Li JP, Chen M, Wu M, Shi Y, Li W, et al. Detecting tumor antigen-specific T cells via interaction-dependent fucosyl-biotinylation. Cell 2020;183:1117–33.E19.

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