한빛사논문
- 조회135
Yumi Oh 1†, Sujeong Kim 2†, Yunjae Kim 2†, Hyun Kim 2†, Dongjun Jang 3, Seungjae Shin 3, Soo-Jin Lee 3, Jiwon Kim 3, Sang Eun Lee 3, Jaeik Oh 4, Yoojin Yang 3, Dohee Kim 3, Hae Rim Jung 1, Sangjin Kim 2, Jihui Kim 2, Kyungchan Min 2, Beomki Cho 2, Hoseok Seo 5,6, Dohyun Han 5,7, Hansoo Park 2,8* and Sung-Yup Cho 1,3,4,9*
1Medical Research Center, Genomic Medicine Institute, Seoul National University College of Medicine, Seoul 03080, Korea
2Department of Biomedical Science and Engineering, Gwangju Institute of Science and Technology (GIST), Gwangju 61005, Korea
3Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul 03080, Korea
4Department of Translational Medicine, Seoul National University College of Medicine, Seoul 03080, Korea
5Department of Transdisciplinary Medicine, Seoul National University Hospital, Seoul 03080, Korea
6Interdisciplinary Program in Neuroscience, College of Natural Sciences, Seoul National University, Seoul 08826, Korea
7Department of Medicine, Seoul National University College of Medicine, Seoul 03080, Korea
8Genome&Company, Suwon 16229, Korea
9Cancer Research Institute, Seoul National University, Seoul 03080, Korea
†Yumi Oh, Sujeong Kim, Yunjae Kim and Hyun Kim contributed equally to this work.
*Corresponding authors: correspondence to Hansoo Park or Sung-Yup Cho
Abstract
Background
Immune checkpoint therapy (ICT) provides durable responses in select cancer patients, yet resistance remains a significant challenge, prompting the exploration of underlying molecular mechanisms. Tyrosylprotein sulfotransferase-2 (TPST2), known for its role in protein tyrosine O-sulfation, has been suggested to modulate the extracellular protein-protein interactions, but its specific role in cancer immunity remains largely unexplored.
Methods
To explore tumor cell-intrinsic factors influencing anti-PD1 responsiveness, we conducted a pooled loss-of-function genetic screen in humanized mice engrafted with human immune cells. The responsiveness of cancer cells to interferon-γ (IFNγ) was estimated by evaluating IFNγ-mediated induction of target genes, STAT1 phosphorylation, HLA expression, and cell growth suppression. The sulfotyrosine-modified target gene of TPST2 was identified by co-immunoprecipitation and mass spectrometry. The in vivo effects of TPST2 inhibition were evaluated using mouse syngeneic tumor models and corroborated by bulk and single-cell RNA sequencing analyses.
Results
Through in vivo genome-wide CRISPR screening, TPST2 loss-of-function emerged as a potential enhancer of anti-PD1 treatment efficacy. TPST2 suppressed IFNγ signaling by sulfating IFNγ receptor 1 at Y397 residue, while its downregulation boosted IFNγ-mediated signaling and antigen presentation. Depletion of TPST2 in cancer cells augmented anti-PD1 antibody efficacy in syngeneic mouse tumor models by enhancing tumor-infiltrating lymphocytes. RNA sequencing data revealed TPST2’s inverse correlation with antigen presentation, and increased TPST2 expression is associated with poor prognosis and altered cancer immunity across cancer types.
Conclusions
We propose TPST2’s novel role as a suppressor of cancer immunity and advocate for its consideration as a therapeutic target in ICT-based treatments.
논문정보
- Research article
- 2024년 08월 (BRIC 등록일 2024-08-05)
- 국내 연구진
- 의약학 > 종양의학
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