연구성과 홍보

Mol Cancer. 2024 Aug 2;23(1):155.

Title : Genome-wide CRISPR screening identifies tyrosylprotein sulfotransferase-2 as a target for augmenting anti-PD1 efficacy

Authors : Yumi Oh#1, Sujeong Kim#2, Yunjae Kim#2, Hyun Kim#2, Dongjun Jang3, Seungjae Shin3, Soo-Jin Lee3, Jiwon Kim3, Sang Eun Lee3, Jaeik Oh4, Yoojin Yang3, Dohee Kim3, Hae Rim Jung1, Sangjin Kim2, Jihui Kim2, Kyungchan Min2, Beomki Cho2, Hoseok Seo5,6, Dohyun Han5,7, Hansoo Park8,9*, Sung-Yup Cho10,11,12,13*

Affiliations :

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.

8Department of Biomedical Science and Engineering, Gwangju Institute of Science and Technology (GIST), Gwangju, 61005, Korea.

9Genome&Company, Suwon, 16229, Korea.

10Medical Research Center, Genomic Medicine Institute, Seoul National University College of Medicine, Seoul, 03080, Korea.

11Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul, 03080, Korea.

12Department of Translational Medicine, Seoul National University College of Medicine, Seoul, 03080, Korea.

13Cancer Research Institute, Seoul National University, Seoul, 03080, Korea.

DOI: 10.1186/s12943-024-02068-x.

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.