2024년 10월 연구원 논문
오유미 책임연구원 (유전체의학연구소)
Genome-wide CRISPR screening identifies tyrosylprotein sulfotransferase-2 as a target for augmenting anti-PD1 efficacy
Molecular Cancer
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.