Clonal replacement of tumor-specific T cells following PD-1 blockade

By K. Yost, Ansuman T. Satpathy, Daniel K. Wells, Yanyan Qi, Chunlin Wang, R. Kageyama, K. McNamara, Jeffrey M. Granja, K. Sarin, Ryanne A. Brown and 6 more. Nature Medicine, 2019

1,316 citations recorded by the source corpus.

Immunotherapies that block inhibitory checkpoint receptors on T cells have transformed the clinical care of patients with cancer1. However, whether the T cell response to checkpoint blockade relies on reinvigoration of pre-existing tumor-infiltrating lymphocytes or on recruitment of novel T cells remains unclear2–4. Here we performed paired single-cell RNA and T cell receptor sequencing on 79,046 cells from site-matched tumors from patients with basal or squamous cell carcinoma before and after anti-PD-1 therapy. Tracking T cell receptor clones and transcriptional phenotypes revealed coupling of tumor recognition, clonal expansion and T cell dysfunction marked by clonal expansion of CD8+CD39+ T cells, which co-expressed markers of chronic T cell activation and exhaustion. However, the expansion of T cell clones did not derive from pre-existing tumor-infiltrating T lymphocytes; instead, the expanded clones consisted of novel clonotypes that had not previously been observed in the same tumor. Clonal replacement of T cells was preferentially observed in exhausted CD8+ T cells and evident in patients with basal or squamous cell carcinoma. These results demonstrate that pre-existing tumor-specific T cells may have limited reinvigoration capacity, and that the T cell response to checkpoint blockade derives from a distinct repertoire of T cell clones that may have just recently entered the tumor. Following anti-PD-1 therapy in patients with basal or squamous cell carcinoma, the CD8+ T cell response largely consists of an expanded and exhausted repertoire of new T cell clones.

Subfields: Immunology, Oncology

View Paper: https://www.semanticscholar.org/paper/8f10d548874183020c8b5d81bbf19f421fd8e6c5

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In Immunology

1. D. Pardoll
2. Janis Taube
3. S. Topalian
4. M. Hellmann
5. A. Schoenfeld
6. Lieping Chen
7. Antoni Ribas
8. J. Wolchok

In Oncology

1. D. Pardoll
2. Janis Taube
3. S. Topalian
4. M. Hellmann
5. A. Schoenfeld
6. Lieping Chen
7. Antoni Ribas
8. J. Wolchok

Citations in the corpus

• Acquired Resistance to Immune Checkpoint Inhibitors (2020, background): “PD-L1 expression, tumor mutational burden, tumor infiltrating lymphocytes (TILs) or related gene expression signatures have been explored as potential predictors and various other markers are currently under investigation (Chen et al., 2016; Cristescu et al., 2018; Garon et al., 2015; Hugo et al., 2”
• Tumor-infiltrating lymphocytes in the immunotherapy era (2020, background): “Accordingly, single-cell RNA and TCR sequencing from site-matched tumors after anti-PD1 treatment revealed expansion of CD8CD39 T cells, yet these T cell clones did not derive from pre-existing intratumoral T cells, suggesting that they were derived from peripheral T cells.(198) Similarly, high TCR ”
• Multimodal Analysis of Composition and Spatial Architecture in Human Squamous Cell Carcinoma (2020, background): “Natural killer (NK) and T cell clusters included CD4 and CD8 conventional and exhausted T cells, regulatory T cells (Treg), and naive-like T cells (Figure 1D), all bearing resemblance to subsets from prior solid tumor scRNA-seq studies (Guo et al., 2018; Puram et al., 2017; Savas et al., 2018; Tiros”
• TISCH: a comprehensive web resource enabling interactive single-cell transcriptome visualization of tumor microenvironment (2020, methodology): “The marker genes of each cell type were collected from the published articles (23-25) and curated manually (Supplementary Table S3, S4).”