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Single-cell transcriptome analysis revealed a role of the transcription factor TOX in promoting CD8+ T-cell exhaustion in cancer

Kyungsoo Kim, Seyeon Park, Ga Min Kim, Su Myeong Park, Seong Yong Park, Da Hee Kim, Young Min Park, Yoon Woo Koh, Hye Ryun Kim, Sang-Jun Ha, Insuk Lee
doi: https://doi.org/10.1101/641316
Kyungsoo Kim
Department of Biotechnology, College of Life Science & Biotechnology, Yonsei University, Seoul 03722, Korea
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Seyeon Park
Department of Biochemistry, College of Life Science & Biotechnology, Yonsei University, Seoul 03722, Korea
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Ga Min Kim
Division of Medical Oncology, Department of Internal Medicine, Yonsei Cancer Center, Yonsei University College of Medicine, Seoul 03722, Korea
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Su Myeong Park
Division of Medical Oncology, Department of Internal Medicine, Yonsei Cancer Center, Yonsei University College of Medicine, Seoul 03722, Korea
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Seong Yong Park
Department of Thoracic and Cardiovascular Surgery, Yonsei University College of Medicine, Seoul 03722, Korea
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Da Hee Kim
Department of Otorhinolaryngology, Yonsei University College of Medicine, Seoul 03722, Korea
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Young Min Park
Department of Otorhinolaryngology, Yonsei University College of Medicine, Seoul 03722, Korea
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Yoon Woo Koh
Department of Otorhinolaryngology, Yonsei University College of Medicine, Seoul 03722, Korea
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Hye Ryun Kim
Division of Medical Oncology, Department of Internal Medicine, Yonsei Cancer Center, Yonsei University College of Medicine, Seoul 03722, Korea
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Sang-Jun Ha
Department of Biochemistry, College of Life Science & Biotechnology, Yonsei University, Seoul 03722, Korea
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  • For correspondence: insuklee@yonsei.ac.kr sjha@yonsei.ac.kr
Insuk Lee
Department of Biotechnology, College of Life Science & Biotechnology, Yonsei University, Seoul 03722, KoreaDepartment of Biomedical Systems Informatics, Yonsei University College of Medicine, Seoul 03722, Korea
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  • For correspondence: insuklee@yonsei.ac.kr sjha@yonsei.ac.kr
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ABSTRACT

Background Functional states of T cells are heterogeneous in tumor microenvironment. Immune checkpoint inhibitor (ICI) can reinvigorate only stem-like exhausted T cells, suggesting that impeding progress of exhaustion will improve immunotherapy efficacy. Transcription factors promoting T-cell exhaustion could be potential targets for delaying the process, improving efficacy of ICI.

Methods Analyzing single-cell transcriptome data derived from melanoma and non-small cell lung cancer (NSCLC), we divided tumor-infiltrating CD8+ T-cell population by PDCD1 (also known as PD-1) expression level into PDCD1-high cells and PDCD1-low cells and identified differentially expressed genes as candidate factors promoting intratumoral T-cell exhaustion. Co-expression of candidate genes with immune checkpoint molecules among tumor-infiltrating CD8+ T cells was confirmed by single-cell trajectory analysis and flow-cytometry analysis. Loss-of-function effect of the candidate regulator was examined by cell-based knockdown assay. Clinical effect of the candidate regulator was evaluated based on overall survival and anti-PD-1 responses.

Results We identified TOX among the most differentially expressed transcription factors between PDCD1-high subset and PDCD1-low subset of tumor-infiltrating CD8+ T cells in melanoma and NSCLC. TOX expression level tend to increase as CD8+ T cells become more exhausted. Flow-cytometry analysis of tumor-infiltrating T cells showed correlation of TOX expression with severity of intratumoral T-cell exhaustion. TOX knockdown resulted in downregulation of PD-1 and TIM-3, suggesting that TOX promotes intratumoral T-cell exhaustion by inducing immune checkpoint molecules. Finally, we found that TOX expression in tumor-infiltrating T cells was predictive for overall survival and anti-PD-1 efficacy in melanoma and NSCLC.

Conclusions We found TOX to promote intratumoral CD8+ T-cell exhaustion via positive regulation of PD-1—TIM-3 cooperation, suggesting that inhibition of TOX potentially impede T-cell exhaustion and improve efficacy of ICI. In addition, TOX expression in tumor-infiltrating T cells would be a useful feature for patient stratification in anti-tumor treatments including anti-PD-1 immunotherapy.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC 4.0 International license.
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Posted May 17, 2019.
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Single-cell transcriptome analysis revealed a role of the transcription factor TOX in promoting CD8+ T-cell exhaustion in cancer
Kyungsoo Kim, Seyeon Park, Ga Min Kim, Su Myeong Park, Seong Yong Park, Da Hee Kim, Young Min Park, Yoon Woo Koh, Hye Ryun Kim, Sang-Jun Ha, Insuk Lee
bioRxiv 641316; doi: https://doi.org/10.1101/641316
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Single-cell transcriptome analysis revealed a role of the transcription factor TOX in promoting CD8+ T-cell exhaustion in cancer
Kyungsoo Kim, Seyeon Park, Ga Min Kim, Su Myeong Park, Seong Yong Park, Da Hee Kim, Young Min Park, Yoon Woo Koh, Hye Ryun Kim, Sang-Jun Ha, Insuk Lee
bioRxiv 641316; doi: https://doi.org/10.1101/641316

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