Highlights
- •Human iCCA is preferentially infiltrated by CD4+ FOXP3+ Tregs showing a highly activated phenotype.
- •Tumor Tregs display a gene program and transcription factor activities indicating superior immunosuppressive potential.
- •MEOX1 transcription factor specifies the transcriptional and genetic identity of tumor Tregs.
- •MEOX1-induced Tregs strongly correlate with worse overall survival in iCCA.
Background & Aims
The landscape and function of the immune infiltrate of intrahepatic cholangiocarcinoma
(iCCA), a rare, yet aggressive tumor of the biliary tract, remains poorly characterized,
limiting development of successful immunotherapies. Herein, we aimed to define the
molecular characteristics of tumor-infiltrating leukocytes with a special focus on
CD4+ regulatory T cells (Tregs).
Methods
We used high-dimensional single-cell technologies to characterize the T-cell and myeloid
compartments of iCCA tissues, comparing these with their tumor-free peritumoral and
circulating counterparts. We further used genomics and cellular assays to define the
iCCA-specific role of a novel transcription factor, mesenchyme homeobox 1 (MEOX1),
in Treg biology.
Results
We found poor infiltration of putative tumor-specific CD39+ CD8+ T cells accompanied
by abundant infiltration of hyperactivated CD4+ Tregs. Single-cell RNA-sequencing
identified an altered network of transcription factors in iCCA-infiltrating compared
to peritumoral T cells, suggesting reduced effector functions by tumor-infiltrating
CD8+ T cells and enhanced immunosuppression by CD4+ Tregs. Specifically, we found
that expression of MEOX1 was highly enriched in tumor-infiltrating Tregs, and demonstrated
that MEOX1 overexpression is sufficient to reprogram circulating Tregs to acquire
the transcriptional and epigenetic landscape of tumor-infiltrating Tregs. Accordingly,
enrichment of the MEOX1-dependent gene program in Tregs was strongly associated with
poor prognosis in a large cohort of patients with iCCA.
Conclusions
We observed abundant infiltration of hyperactivated CD4+ Tregs in iCCA tumors along
with reduced CD8+ T-cell effector functions. Interfering with hyperactivated Tregs
should be explored as an approach to enhance antitumor immunity in iCCA.
Lay summary
Immune cells have the potential to slow or halt the progression of tumors. However,
some tumors, such as intrahepatic cholangiocarcinoma, are associated with very limited
immune responses (and infiltration of cancer-targeting immune cells). Herein, we show
that a specific population of regulatory T cells (a type of immune cell that actually
suppresses the immune response) are hyperactivated in intrahepatic cholangiocarcinoma.
Targeting these cells could enable cancer-targeting immune cells to act more effectively
and should be looked at as a potential therapeutic approach to this aggressive cancer
type.
Graphical abstract
Graphical Abstract
Keywords
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Article info
Publication history
Published online: June 20, 2022
Accepted:
May 31,
2022
Received in revised form:
May 24,
2022
Received:
September 10,
2021
Footnotes
Author names in bold designate shared co-first authorship
Identification
Copyright
© 2022 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.
