ISSN: 1838-7640Theranostics
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Theranostics 2021; 11(10):4957-4974. doi:10.7150/thno.55075 This issue Cite
Research Paper
Single-cell transcriptome analysis of the heterogeneous effects of differential expression of tumor PD-L1 on responding TCR-T cells
1. BGI-Shenzhen, Shenzhen 518083, China.
2. BGI Education Center, University of Chinese Academy of Sciences, Shenzhen 518083, China.
3. Guangdong Provincial Key Laboratory of Human Disease Genomics, Shenzhen Key Laboratory of Genomics.
4. Guangdong Provincial Key Laboratory of Genome Read and Write, BGI-Shenzhen, Shenzhen 518083, China.
5. Shenzhen Bay Laboratory, Shenzhen 518132, China.
*These authors contributed equally to this work.
Citation:
Ding R, Liu S, Wang S, Chen H, Wang F, Xu Q, Zhu L, Dong X, Gu Y, Zhang X, Chao CC, Gao Q. Single-cell transcriptome analysis of the heterogeneous effects of differential expression of tumor PD-L1 on responding TCR-T cells. Theranostics 2021; 11(10):4957-4974. doi:10.7150/thno.55075. https://www.thno.org/v11p4957.htm
Other stylesAbstract
Rationale: TCR-T cell therapy plays a critical role in the treatment of malignant cancers. However, it is unclear how TCR-T cells are affected by PD-L1 molecule in the tumor environment. We performed an in-depth evaluation on how differential expressions of tumor PD-L1 can affect the functionality of T cells.
Methods: We used MART-1-specific TCR-T cells (TCR-TMART-1), stimulated with MART-127-35 peptide-loaded MEL-526 tumor cells, expressing different proportions of PD-L1, to perform cellular assays and high-throughput single-cell RNA sequencing.
Results: Different clusters of activated or cytotoxic TCR-TMART-1 responded divergently when stimulated with tumor cells expressing different percentages of PD-L1 expression. Compared to control T cells, TCR-TMART-1 were more sensitive to exhaustion, and secreted not only pro-inflammatory cytokines but also anti-inflammatory cytokines with increasing proportions of PD-L1+ tumor cells. The gene profiles of chemokines were modified by increased expression of tumor PD-L1, which concurrently downregulated pro-inflammatory and anti-inflammatory transcription factors. Furthermore, increased expression of tumor PD-L1 showed distinct effects on different inhibitory checkpoint molecules (ICMs). In addition, there was a limited correlation between the enrichment of cell death signaling in tumor cells and T cells and increased tumor PD-L1 expression.
Conclusion: Overall, though the effector functionality of TCR-T cells was suppressed by increased expression percentages of tumor PD-L1 in vitro, scRNA-seq profiles revealed that both the anti-inflammatory and pro-inflammatory responses were triggered by a higher expression of tumor PD-L1. This suggests that the sole blockade of tumor PD-L1 might inhibit not only the anti-inflammatory response but also the pro-inflammatory response in the complicated tumor microenvironment. Thus, the outcome of PD-L1 intervention may depend on the final balance among the highly dynamic and heterogeneous immune regulatory circuits.
Keywords: TCR-T, PD-L1, differential expression, single-cell RNA sequencing, melanoma
Citation styles
APA
Ding, R., Liu, S., Wang, S., Chen, H., Wang, F., Xu, Q., Zhu, L., Dong, X., Gu, Y., Zhang, X., Chao, C.C., Gao, Q. (2021). Single-cell transcriptome analysis of the heterogeneous effects of differential expression of tumor PD-L1 on responding TCR-T cells. Theranostics, 11(10), 4957-4974. https://doi.org/10.7150/thno.55075.
ACS
Ding, R.; Liu, S.; Wang, S.; Chen, H.; Wang, F.; Xu, Q.; Zhu, L.; Dong, X.; Gu, Y.; Zhang, X.; Chao, C.C.; Gao, Q. Single-cell transcriptome analysis of the heterogeneous effects of differential expression of tumor PD-L1 on responding TCR-T cells. Theranostics 2021, 11 (10), 4957-4974. DOI: 10.7150/thno.55075.
NLM
Ding R, Liu S, Wang S, Chen H, Wang F, Xu Q, Zhu L, Dong X, Gu Y, Zhang X, Chao CC, Gao Q. Single-cell transcriptome analysis of the heterogeneous effects of differential expression of tumor PD-L1 on responding TCR-T cells. Theranostics 2021; 11(10):4957-4974. doi:10.7150/thno.55075. https://www.thno.org/v11p4957.htm
CSE
Ding R, Liu S, Wang S, Chen H, Wang F, Xu Q, Zhu L, Dong X, Gu Y, Zhang X, Chao CC, Gao Q. 2021. Single-cell transcriptome analysis of the heterogeneous effects of differential expression of tumor PD-L1 on responding TCR-T cells. Theranostics. 11(10):4957-4974.
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