[Abstract unavailable

Summary Responses to anti-PD-1 immunotherapy occur but are infrequent in bladder cancer. The specific T cells that mediate tumor rejection are unknown. T cells from human bladder tumors and non-malignant tissue were assessed with single-cell RNA and paired T cell receptor (TCR) sequencing of 30,604 T cells from 7 patients. We find that the states and repertoires of CD8 + T cells are not distinct in tumors compared with non-malignant tissues. In contrast, single-cell analysis of CD4 + T cells demonstrates several tumor-specific states, including multiple distinct states of regulatory T cells. Surprisingly, we also find multiple cytotoxic CD4 + T cell states that are clonally expanded. These CD4 + T cells can kill autologous tumors in an MHC class II-dependent fashion and are suppressed by regulatory T cells. Further, a gene signature of cytotoxic CD4 + T cells in tumors predicts a clinical response in 244 metastatic bladder cancer patients treated with anti-PD-L1.

The UCSF COMET Consortium, Michael Matthay, David J. E rl e , P re scot t G. Woodruff, Charles Langelier, Kirsten K an ge la ri s, C ar ol yn M.

Systemic lupus erythematosus (SLE) is a heterogeneous autoimmune disease. Knowledge of circulating immune cell types and states associated with SLE remains incomplete. We profiled more than 1.2 million peripheral blood mononuclear cells (162 cases, 99 controls) with multiplexed single-cell RNA sequencing (mux-seq). Cases exhibited elevated expression of type 1 interferon–stimulated genes (ISGs) in monocytes, reduction of naïve CD4 + T cells that correlated with monocyte ISG expression, and expansion of repertoire-restricted cytotoxic GZMH + CD8 + T cells. Cell type–specific expression features predicted case-control status and stratified patients into two molecular subtypes. We integrated dense genotyping data to map cell type–specific cis–expression quantitative trait loci and to link SLE-associated variants to cell type–specific expression. These results demonstrate mux-seq as a systematic approach to characterize cellular composition, identify transcriptional signatures, and annotate genetic variants associated with SLE.