Using scRNAseq with TCR-based lineage tracking, Liu, Hu, and Feng et al. characterized the temporal dynamics of T cells from dissociated tumor biopsies of 36 patients with NSCLC following combination therapy with anti-PD-1 and chemotherapy. Two precursor exhausted T cell states (Texp) with high GZMK expression and low expression of exhaustion markers were identified. Responsive tumors showed an increase in Texp cells with high expression of CXCL13. Increased Texp cells in responsive tumors following treatment was likely due to the local expansion and infiltration of pre-existing and new clonotypes from peripheral Texp cells, but not reinvigoration of terminally exhausted T cells.
Contributed by Shishir Pant
ABSTRACT: Anti-PD-1 treatment has shown unprecedented clinical success in the treatment of non-small-cell lung cancer (NSCLC), but the underlying mechanisms remain incompletely understood. Here, we performed temporal single-cell RNA and paired T-cell receptor sequencing on 47 tumor biopsies from 36 patients with NSCLC following PD-1-based therapies. We observed increased levels of precursor exhausted T (Texp) cells in responsive tumors after treatment, characterized by low expression of coinhibitory molecules and high expression of GZMK. By contrast, nonresponsive tumors failed to accumulate Texp cells. Our data suggested that Texp cells were unlikely to be derived from the reinvigoration of terminally exhausted cells; instead, they were accumulated by (1) local expansion and (2) replenishment by peripheral T cells with both new and pre-existing clonotypes, a phenomenon we named clonal revival. Our study provides insights into mechanisms underlying PD-1-based therapies, implicating clonal revival and expansion of Texp cells as steps to improve NSCLC treatment.
Author Info: (1) BIOPIC, Beijing Advanced Innovation Center for Genomics, School of Life Sciences, Peking University, Beijing, China. (2) Department of Bio-therapeutic, The First Medical Center
Author Info: (1) BIOPIC, Beijing Advanced Innovation Center for Genomics, School of Life Sciences, Peking University, Beijing, China. (2) Department of Bio-therapeutic, The First Medical Center, Chinese PLA General Hospital, Beijing, China. (3) Department of Tumor Biological Treatment, The Third Affiliated Hospital of Soochow University, Changzhou, Jiangsu, China. (4) Department of Thoracic Surgery, The First Medical Center, Chinese PLA General Hospital, Beijing, China. (5) Department of Oncology, The First Medical Center, Chinese PLA General Hospital, Beijing, China. (6) Peking-Tsinghua Center for Life Sciences, Academy for Advanced Interdisciplinary Studies, Peking University, Beijing, China. (7) Department of Cancer Immunology, Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, CT, USA. (8) Cancer Research Institute, Shenzhen Bay Lab, Shenzhen, China. 9These authors contributed equally: Baolin Liu, Xueda Hu, Kaichao Feng. :envelope📧 hanwdrsw69@yahoo.com; zemin@pku.edu.cn
