Systematic interrogation of tumor-infiltrating lymphocytes is key to the development of immunotherapies and the prediction of their clinical responses in cancers. Here, we perform deep single-cell RNA sequencing on 5,063 single T cells isolated from peripheral blood, tumor, and adjacent normal tissues from six hepatocellular carcinoma patients. The transcriptional profiles of these individual cells, coupled with assembled T cell receptor (TCR) sequences, enable us to identify 11 T cell subsets based on their molecular and functional properties and delineate their developmental trajectory. Specific subsets such as exhausted CD8 T cells and Tregs are preferentially enriched and potentially clonally expanded in hepatocellular carcinoma (HCC), and we identified signature genes for each subset. One of the genes, layilin, is upregulated on activated CD8 T cells and Tregs and represses the CD8 T cell functions in vitro. This compendium of transcriptome data provides valuable insights and a rich resource for understanding the immune landscape in cancers.

Developing therapeutics against SARS-CoV-2 could be guided by the distribution of epitopes, not only on the receptor binding domain (RBD) of the Spike (S) protein, but also across the full Spike (S) protein. We isolated and characterized monoclonal antibodies (mAbs) from ten convalescent COVID-19 patients. Three mAbs showed neutralizing activities against authentic SARS-CoV-2. An mAb, named 4A8, exhibits high neutralization potency against both authentic and pseudotyped SARS-CoV-2, but does not bind the RBD. We defined the epitope of 4A8 as the N terminal domain (NTD) of the S protein by determining its cryo-EM structure in complex with the S protein to an overall resolution of 3.1 Angstrom and local resolution of 3.3 Angstrom for the 4A8-NTD interface. This points to the NTD as a promising target for therapeutic mAbs against COVID-19.

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Cancer immunotherapies have shown sustained clinical responses in treating non-small-cell lung cancer, but efficacy varies and depends in part on the amount and properties of tumor infiltrating lymphocytes. To depict the baseline landscape of the composition, lineage and functional states of tumor infiltrating lymphocytes, here we performed deep single-cell RNA sequencing for 12,346 T cells from 14 treatment-naïve non-small-cell lung cancer patients. Combined expression and T cell antigen receptor based lineage tracking revealed a significant proportion of inter-tissue effector T cells with a highly migratory nature. As well as tumor-infiltrating CD8 T cells undergoing exhaustion, we observed two clusters of cells exhibiting states preceding exhaustion, and a high ratio of "pre-exhausted" to exhausted T cells was associated with better prognosis of lung adenocarcinoma. Additionally, we observed further heterogeneity within the tumor regulatory T cells (Tregs), characterized by the bimodal distribution of TNFRSF9, an activation marker for antigen-specific Tregs. The gene signature of those activated tumor Tregs, which included IL1R2, correlated with poor prognosis in lung adenocarcinoma. Our study provides a new approach for patient stratification and will help further understand the functional states and dynamics of T cells in lung cancer.

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