한빛사논문
- 조회374
Junha Cha,1 Da Hee Kim,2 Gamin Kim,3 Jae-Won Cho,4 Euijeong Sung,1 Seungbyn Baek,1 Min Hee Hong,3 Chang Gon Kim,3 Nam Suk Sim,2 Hyun Jun Hong,2 Jung Eun Lee,3 Martin Hemberg,4 Seyeon Park,5 Sun Ock Yoon,6 Sang-Jun Ha,5 Yoon Woo Koh,2 Hye Ryun Kim,3 Insuk Lee1,7
1Department of Biotechnology, College of Life Science and Biotechnology, Yonsei University, Seoul, Republic of Korea
2Department of Otorhinolaryngology, Yonsei University College of Medicine, Seoul, Republic of Korea
3Division of Medical Oncology, Department of Internal Medicine, Yonsei Cancer Center, Yonsei University College of Medicine, Seoul, Republic of Korea
4The Gene Lay Institute of Immunology and Inflammation, Brigham and Women's Hospital, Massachusetts General Hospital, and Harvard Medical School, Boston, MA, USA
5Department of Biochemistry, College of Life Science and Biotechnology, Yonsei University, Seoul, Republic of Korea
6Department of Pathology, Yonsei University College of Medicine, Seoul, Republic of Korea
7POSTECH Biotech Center, Pohang University of Science and Technology (POSTECH), Pohang, Republic of Korea
JC, DHK and GK contributed equally.
Correspondence to Professor Insuk Lee; Professor Hye Ryun Kim; Professor Yoon Woo Koh; Professor Sang- Jun Ha
Abstract
Background: Oropharyngeal squamous cell carcinoma (OPSCC) induced by human papillomavirus (HPV-positive) is associated with better clinical outcomes than HPV-negative OPSCC. However, the clinical benefits of immunotherapy in patients with HPV-positive OPSCC remain unclear.
Methods: To identify the cellular and molecular factors that limited the benefits associated with HPV in OPSCC immunotherapy, we performed single-cell RNA (n=20) and T-cell receptor sequencing (n=10) analyses of tonsil or base of tongue tumor biopsies prior to immunotherapy. Primary findings from our single-cell analysis were confirmed through immunofluorescence experiments, and secondary validation analysis were performed via publicly available transcriptomics data sets.
Results: We found significantly higher transcriptional diversity of malignant cells among non-responders to immunotherapy, regardless of HPV infection status. We also observed a significantly larger proportion of CD4+ follicular helper T cells (Tfh) in HPV-positive tumors, potentially due to enhanced Tfh differentiation. Most importantly, CD8+ resident memory T cells (Trm) with elevated KLRB1 (encoding CD161) expression showed an association with dampened antitumor activity in patients with HPV-positive OPSCC, which may explain their heterogeneous clinical outcomes. Notably, all HPV-positive patients, whose Trm presented elevated KLRB1 levels, showed low expression of CLEC2D (encoding the CD161 ligand) in B cells, which may reduce tertiary lymphoid structure activity. Immunofluorescence of HPV-positive tumors treated with immune checkpoint blockade showed an inverse correlation between the density of CD161+ Trm and changes in tumor size.
Conclusions: We found that CD161+ Trm counteracts clinical benefits associated with HPV in OPSCC immunotherapy. This suggests that targeted inhibition of CD161 in Trm could enhance the efficacy of immunotherapy in HPV-positive oropharyngeal cancers.
논문정보
- Research article
- 2024년 06월 (BRIC 등록일 2024-06-11)
- 국내(교신)+국외 연구진
- 생명과학 > 유전학
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