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Status |
Public on Sep 27, 2023 |
Title |
In vivo macrophage engineering reshapes the tumor microenvironment leading to eradication of liver metastases [scRNA-seq] |
Organism |
Mus musculus |
Experiment type |
Expression profiling by high throughput sequencing
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Summary |
Liver metastases are associated with poor response to current pharmacological treatments, including immunotherapy. We describe a lentiviral vector (LV) platform to selectively engineer liver macrophages, including Kupffer cells and tumor-associated macrophages (TAMs), to deliver type I interferon (IFNα) to liver metastases. Gene-based IFNα delivery delays the growth of colorectal and pancreatic ductal adenocarcinoma liver metastases in mice. Response to IFNα is associated with TAM immune activation, enhanced MHC-II-restricted antigen presentation and reduced exhaustion of CD8+ T cells. Conversely, increased IL-10 signaling, expansion of Eomes CD4+ T cells, a cell type displaying features of type I regulatory T (Tr1) cells, and CTLA-4 expression are associated with resistance to therapy. Targeting regulatory T cell functions by combinatorial CTLA-4 immune checkpoint blockade and IFNα LV delivery expands tumor-reactive T cells, attaining complete response in most mice. These findings support a promising therapeutic strategy with feasible translation to patients with unmet medical need.
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Overall design |
Single-cell transcriptomics on metastatic liver in three distinct cohorts: (1) Control: Control LV-treated mice, (2) Partial responder: IFNa LV-treated mice with reduced tumor volume as compared to Control and, (3) Resistant: IFNa LV-treated mice with tumor volume similar to Control.
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Contributor(s) |
Kerzel T, Giacca G, Merelli I, Naldini L, Squadrito ML |
Citation(s) |
37863068 |
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Submission date |
Dec 19, 2022 |
Last update date |
Jan 04, 2024 |
Contact name |
Stefano Beretta |
E-mail(s) |
beretta.stefano1@hsr.it
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Organization name |
San Raffaele Telethon Institute for Gene Therapy
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Street address |
Via Olgettina, 60
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City |
Milan |
ZIP/Postal code |
20132 |
Country |
Italy |
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Platforms (1) |
GPL24247 |
Illumina NovaSeq 6000 (Mus musculus) |
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Samples (8)
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GSM6859010 |
Control sample of Tumor liver (Mouse 1) |
GSM6859011 |
Resistant sample of Tumor liver (Mouse 1) |
GSM6859012 |
Control sample of Tumor liver (Mouse 2) |
GSM6859013 |
Partial Responder sample of Tumor liver (Mouse 1) |
GSM6859014 |
Partial Responder sample of Tumor liver (Mouse 2) |
GSM6859015 |
Resistant sample of Tumor liver (Mouse 2) |
GSM6859016 |
Control sample of Tumor liver (Mouse 3) |
GSM6859017 |
Partial Responder sample of Tumor liver (Mouse 3) |
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This SubSeries is part of SuperSeries: |
GSE221360 |
In vivo macrophage engineering reshapes the tumor microenvironment leading to eradication of liver metastases |
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Relations |
BioProject |
PRJNA913955 |