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Single-cell transcriptomic analysis of tissue-resident memory T cells in human lung cancer (Smart-seq2)
James Clarke, Bharat Panwar, Ariel Madrigal, Divya Singh, Ravindra Gujar, Oliver Wood, Serena J. Chee, Simon Eschweiler, Emma V. King, Amiera S. Awad, Christopher J. Hanley, Katy J. McCann, Sourya Bhattacharyya, Edwin Woo, Aiman Alzetani, Grégory Seumois, Gareth J. Thomas, Anusha-Preethi Ganesan, Peter S. Friedmann, Tilman Sanchez-Elsner, Ferhat Ay, Christian H. Ottensmeier, and Pandurangan Vijayan
High numbers of tissue-resident memory T (TRM) cells are associated with better clinical outcomes in cancer patients. However, the molecular characteristics that drive their efficient immune response to tumors are poorly understood. Here, single-cell and bulk transcriptomic analysis of TRM and non-TRM cells present in tumor and normal lung tissue from patients with lung cancer revealed that PD-1–expressing TRM cells in tumors were clonally expanded and enriched for transcripts linked to cell proliferation and cytotoxicity when compared with PD-1–expressing non-TRM cells. This feature was more prominent in the TRM cell subset coexpressing PD-1 and TIM-3, and it was validated by functional assays ex vivo and also reflected in their chromatin accessibility profile. This PD-1+TIM-3+ TRM cell subset was enriched in responders to PD-1 inhibitors and in tumors with a greater magnitude of CTL responses. These data highlight that not all CTLs expressing PD-1 are dysfunctional; on the contrary, TRM cells with PD-1 expression were enriched for features suggestive of superior functionality.