Tumor-Infiltrating T Cells Mimic Tissue-Resident T-cell Heterogeneity

Circulating CD8⁺ T cells come in different types that vary with regard to function and memory potential, but whether tissue-resident memory T (T_rm) cells—which resemble tumor-infiltrating lymphocytes (TIL) in some regards—also exhibit this property has not been established. Using a mouse model of lymphocytic choriomeningitis virus (LCMV) infection, Milner and colleagues found evidence for marked intertemporal and intratemporal heterogeneity in antigen-specific antiviral T_rm cells in the small-intestine intraepithelial lymphocyte population. Early in viral infection, effector T cell–like T_rm cells high in BLIMP1 and low in ID3 (BLIMP1^hiID3^lo) predominated, whereas memory T cell–like BLIMP1^loID3^hi T_rm cells became more prevalent as infection progressed. The T_rm cell types defined by their expression of the transcriptional regulators BLIMP1 and ID3 also had unique transcriptional profiles and differed in other ways: BLIMP1^loID3^hi T_rm cells had enhanced cytokine production and secondary memory potential compared with BLIMP1^hiID3^lo T_rm cells. Notably, the memory T cell–like BLIMP1^loID3^hi T_rm cells were more multifunctional, possessing greater multipotency and the ability to give rise to both circulating and resident T-cell populations upon reinfection. Extending this analysis to a mouse model of melanoma revealed similarly delineated tumor-infiltrating T-cell types, with BLIMP1^hiID3^lo CD8⁺ TILs (similar to the tissue-resident effector T cell–like T_rm cells observed early in infection) exhibiting effector-like behavior and BLIMP1^loID3^hi CD8⁺ TILs (similar to the tissue-resident memory T cell–like T_rm cells observed later in infection) exhibiting memory-like behavior. Transcriptomic analysis showed that the effector-like CD8⁺ TILs had gene-expression signatures akin to those of terminally exhausted T cells, whereas the memory-like CD8⁺ TILs had gene-expression signatures more similar to progenitor-exhausted T cells. In summary, this work identifies T_rm-cell and TIL heterogeneity that carries functional consequences, and this heterogeneity appears to extend to TILs, providing insight into the roles of cells that are critical for antitumor immunity.

Milner JJ, Toma C, He Z, Kurd NS, Nguyen QP, McDonald B, et al. Heterogenous populations of tissue-resident CD8⁺ T cells are generated in response to infection and malignancy. Immunity 2020;52:808–24.E7.

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