Single cell analysis in head and neck cancer reveals potential immune evasion mechanisms during early metastasis

Hong Sheng Quah, Elaine Yiqun Cao, Lisda Suteja, Constance H. Li, Hui Sun Leong, Fui Teen Chong, Shilpi Gupta, Camille Arcinas, John F. Ouyang, Vivian Ang, Teja Celhar, Yunqian Zhao, Hui Chen Tay, Jerry Chan, Takeshi Takahashi, Daniel S. W. Tan, Subhra K. Biswas, Owen J. L. Rackham and N. Gopalakrishna Iyer ()
Additional contact information
Hong Sheng Quah: National Cancer Centre
Elaine Yiqun Cao: Duke-NUS Medical School
Lisda Suteja: National Cancer Centre
Constance H. Li: National Cancer Centre
Hui Sun Leong: National Cancer Centre
Fui Teen Chong: National Cancer Centre
Shilpi Gupta: Agency for Science Technology and Research (A*STAR)
Camille Arcinas: National Cancer Centre
John F. Ouyang: Duke-NUS Medical School
Vivian Ang: Agency for Science Technology and Research (A*STAR)
Teja Celhar: Agency for Science, Technology and Research (A*STAR)
Yunqian Zhao: Agency for Science, Technology and Research (A*STAR)
Hui Chen Tay: Agency for Science, Technology and Research (A*STAR)
Jerry Chan: KK Women’s and Children’s Hospital
Takeshi Takahashi: Central Institute for Experimental Animals (CIEA)
Daniel S. W. Tan: National Cancer Centre
Subhra K. Biswas: Agency for Science Technology and Research (A*STAR)
Owen J. L. Rackham: Duke-NUS Medical School
N. Gopalakrishna Iyer: National Cancer Centre

Nature Communications, 2023, vol. 14, issue 1, 1-19

Abstract: Abstract Profiling tumors at single-cell resolution provides an opportunity to understand complexities underpinning lymph-node metastases in head and neck squamous-cell carcinoma. Single-cell RNAseq (scRNAseq) analysis of cancer-cell trajectories identifies a subpopulation of pre-metastatic cells, driven by actionable pathways including AXL and AURK. Blocking these two proteins blunts tumor invasion in patient-derived cultures. Furthermore, scRNAseq analyses of tumor-infiltrating CD8 + T-lymphocytes show two distinct trajectories to T-cell dysfunction, corroborated by their clonal architecture based on single-cell T-cell receptor sequencing. By determining key modulators of these trajectories, followed by validation using external datasets and functional experiments, we uncover a role for SOX4 in mediating T-cell exhaustion. Finally, interactome analyses between pre-metastatic tumor cells and CD8 + T-lymphocytes uncover a putative role for the Midkine pathway in immune-modulation and this is confirmed by scRNAseq of tumors from humanized mice. Aside from specific findings, this study demonstrates the importance of tumor heterogeneity analyses in identifying key vulnerabilities during early metastasis.

Date: 2023
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DOI: 10.1038/s41467-023-37379-y

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