A group of researchers from the Stanford University School of Medicine, Stanford, CA, USA reported in a Letter on 29 July 2019 in the Nature Medicine that pre-existing tumour-specific T cells may have limited reinvigoration capacity, and that the T cell response to immune checkpoint blockade derives from a distinct repertoire of T cell clones that may have just recently entered the tumour.
The authors wrote in the study background that therapies that block inhibitory checkpoint receptors on T cells have transformed the clinical care of patients with cancer. However, whether the T cell response to immune checkpoint blockade relies on reinvigoration of pre-existing tumour-infiltrating lymphocytes or on recruitment of novel T cells was unclear.
It prompted the study team to perform paired single-cell RNA and T cell receptor sequencing on 79,046 cells from site-matched tumours from patients with basal or squamous cell carcinoma before and after anti-PD-1 monoclonal antibodies.
Tracking T cell receptor clones and transcriptional phenotypes revealed coupling of tumour 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 tumour-infiltrating T lymphocytes. Instead, the expanded clones consisted of novel clonotypes that had not previously been observed in the same tumour.
Clonal replacement of T cells was preferentially observed in exhausted CD8+ T cells and evident in patients with basal or squamous cell carcinoma.
The study was supported by the Parker Institute for Cancer Immunotherapy, the Michelson Foundation and multiple grants from the US National Institutes of Health (NIH). Cell sorting for this project was done on instruments in the Stanford Shared FACS Facility. Sequencing was performed by the Stanford Functional Genomics Facility supported by NIH grant.
All ensemble and scRNA-seq data have been deposited in the GEO and are available under accession number GSE123814. Exome-sequencing data have been deposited in the Sequence Read Archive and are available under accession number PRJNA533341. Bulk TCR-seq data can be accessed through the ImmuneACCESS database of Adaptive Biotechnologies[SJ-E3] .
Yost KE, Satpathy AT, Wells DK, et al. Clonal replacement of tumor-specific T cells following PD-1 blockade. Nature Medicine; Published online 29 July 2019.doi: 10.1038/s41591-019-0522-3.