Defining T cell states associated with response to checkpoint immunotherapy in melanoma

By Moshe Sade-Feldman, K. Yizhak, Stacey L. Bjorgaard, John P. Ray, Carl G. de Boer, Russell W. Jenkins, David J. Lieb, Jonathan H. Chen, Dennie T. Frederick, Michal Barzily-Rokni and 25 more. Cell, 2018

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SUMMARY Treatment of cancer has been revolutionized by immune checkpoint blockade therapies. Despite the high rate of response in advanced melanoma, the majority of patients succumb to disease. To identify factors associated with success or failure of checkpoint therapy, we profiled transcriptomes of 16,291 individual immune cells from 48 tumor samples of melanoma patients treated with checkpoint inhibitors. Two distinct states of CD8+ T cells were defined by clustering, and associated with patient tumor regression or progression. A single transcription factor, TCF7, was visualized within CD8+ T cells in fixed tumor samples and predicted positive clinical outcome in an independent cohort of checkpoint-treated patients. We delineated the epigenetic landscape and clonality of these T cell states, and demonstrated enhanced anti-tumor immunity by targeting novel combinations of factors in exhausted cells. Our study of immune cell transcriptomes from tumors demonstrates a strategy for identifying predictors, mechanisms and targets for enhancing checkpoint immunotherapy.

Subfields: Immunology, Oncology

View Paper: https://www.semanticscholar.org/paper/597c50c4b74e40f3bf8ac874f3b6ab2f9b6dd211

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Citations in the corpus

Acquired Resistance to Immune Checkpoint Inhibitors (2020, background): “profiled the transcriptomes of individual immune cells (48 samples from 32 patients with melanoma) receiving immunotherapy, enabling the detection of individual T cell populations and associated markers associated with ICI responders and non-responders (Sade-Feldman et al., 2018).”
Developmental Relationships of Four Exhausted CD8+ T Cell Subsets Reveals Underlying Transcriptional and Epigenetic Landscape Control Mechanisms (2020, positive): “Multiple comparative analysis were performed using datasets publicly available through the Gene Expression Omnibus (GEO) database (https://www.ncbi.nlm.nih.gov/gds) under the following accession numbers: CXCR5+Tim3− and CXCR5−Tim3+ (GSE84105)(Im et al., 2016), MPEC and SLEC (GSE8678)(Joshi et al., 2”
TISCH: a comprehensive web resource enabling interactive single-cell transcriptome visualization of tumor microenvironment (2020, background): “A recent study performed on melanoma patients treated with checkpoint therapy showed that patients with high TCF7+CD8+ T cells are associated with favorable clinical outcomes after treatment (8).”
Tumor-infiltrating lymphocytes in the immunotherapy era (2020, background): “57,58,64 This is supported by a high-dimensional single-cell RNA analysis of melanoma tumors treated with checkpoint inhibition, which identified TCF7CD8 T cells in particular to be associated with better tumor regression and overall response in checkpoint-treated patients.(60) Taken together, these”
Pan-cancer single-cell landscape of tumor-infiltrating T cells (2021, positive): “Reanalysis of published data of PD-1 antibody treatment for melanoma (42) indicated that responsive tumors had a lower frequency of terminal Tex cells and a higher frequency of naïve T cells (Fig.”