Immunostimulatory effects of targeted thorium-227 conjugates as single agent and in combination with anti-PD-L1 therapy Article Swipe
Pascale Lejeune
,
Véronique Cruciani
,
Axel Berg‐Larsen
,
Andreas Schlicker
,
Anne Mobergslien
,
Lisa Bartnitzky
,
Sandra Berndt
,
Sabine Zitzmann-Kolbe
,
Claudia Kamfenkel
,
Stefan Stargard
,
Stefanie Hammer
,
Jennifer Solgaard Jørgensen
,
Malene Jackerott
,
Carsten H. Nielsen
,
Christoph A. Schatz
,
Hartwig Hennekes
,
Jenny Karlsson
,
Alan Cuthbertson
,
Dominik Mumberg
,
Urs B. Hagemann
·
YOU?
·
· 2021
· Open Access
·
· DOI: https://doi.org/10.1136/jitc-2021-002387
YOU?
·
· 2021
· Open Access
·
· DOI: https://doi.org/10.1136/jitc-2021-002387
Background Targeted thorium-227 conjugates (TTCs) are an emerging class of targeted alpha therapies (TATs). Their unique mode of action (MoA) is the induction of difficult-to-repair clustered DNA double-strand breaks. However, thus far, their effects on the immune system are largely unknown. Here, we investigated the immunostimulatory effects of the mesothelin-targeted thorium-227 conjugate (MSLN-TTC) in vitro and in vivo in monotherapy and in combination with an inhibitor of the immune checkpoint programmed death receptor ligand 1 (PD-L1) in immunocompetent mice. Methods The murine cell line MC38 was transfected with the human gene encoding for MSLN (hMSLN) to enable binding of the non-cross-reactive MSLN-TTC. The immunostimulatory effects of MSLN-TTC were studied in vitro on human cancer cell lines and MC38-hMSLN cells. The efficacy and MoA of MSLN-TTC were studied in vivo as monotherapy or in combination with anti-PD-L1 in MC38-hMSLN tumor-bearing immunocompetent C57BL/6 mice. Experiments were supported by RNA sequencing, flow cytometry, immunohistochemistry, mesoscale, and TaqMan PCR analyses to study the underlying immunostimulatory effects. In vivo depletion of CD8+ T cells and studies with Rag2/Il2Rg double knockout C57BL/6 mice were conducted to investigate the importance of immune cells to the efficacy of MSLN-TTC. Results MSLN-TTC treatment induced upregulation of DNA sensing pathway transcripts ( IL-6 , CCL20 , CXCL10 , and stimulator of interferon genes ( STING )-related genes) in vitro as determined by RNASeq analysis. The results, including phospho-STING activation, were confirmed on the protein level. Danger-associated molecular pattern molecules were upregulated in parallel, leading to dendritic cell (DC) activation in vitro . MSLN-TTC showed strong antitumor activity (T:C 0.38, p<0.05) as a single agent in human MSLN-expressing MC38 tumor-bearing immunocompetent mice. Combining MSLN-TTC with anti-PD-L1 further enhanced the efficacy (T:C 0.08, p<0.001) as evidenced by the increased number of tumor-free surviving animals. MSLN-TTC monotherapy caused migration of CD103+ cDC1 DCs and infiltration of CD8+ T cells into tumors, which was enhanced on combination with anti-PD-L1. Intriguingly, CD8+ T-cell depletion decreased antitumor efficacy. Conclusions These in vitro and in vivo data on MSLN-TTC demonstrate that the MoA of TTCs involves activation of the immune system. The findings are of relevance for other targeted radiotherapies and may guide clinical combination strategies.
Related Topics
Concepts
Mesothelin
Cancer research
In vivo
Immune checkpoint
Immune system
Pseudomonas exotoxin
CD8
Medicine
Immunotherapy
In vitro
Biology
Antigen
Immunology
Cytotoxicity
Biochemistry
Biotechnology
Metadata
- Type
- article
- Language
- en
- Landing Page
- https://doi.org/10.1136/jitc-2021-002387
- https://jitc.bmj.com/content/jitc/9/10/e002387.full.pdf
- OA Status
- gold
- Cited By
- 48
- References
- 43
- Related Works
- 10
- OpenAlex ID
- https://openalex.org/W3203731043
All OpenAlex metadata
Raw OpenAlex JSON
- OpenAlex ID
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https://openalex.org/W3203731043Canonical identifier for this work in OpenAlex
- DOI
-
https://doi.org/10.1136/jitc-2021-002387Digital Object Identifier
- Title
-
Immunostimulatory effects of targeted thorium-227 conjugates as single agent and in combination with anti-PD-L1 therapyWork title
- Type
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articleOpenAlex work type
- Language
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enPrimary language
- Publication year
-
2021Year of publication
- Publication date
-
2021-10-01Full publication date if available
- Authors
-
Pascale Lejeune, Véronique Cruciani, Axel Berg‐Larsen, Andreas Schlicker, Anne Mobergslien, Lisa Bartnitzky, Sandra Berndt, Sabine Zitzmann-Kolbe, Claudia Kamfenkel, Stefan Stargard, Stefanie Hammer, Jennifer Solgaard Jørgensen, Malene Jackerott, Carsten H. Nielsen, Christoph A. Schatz, Hartwig Hennekes, Jenny Karlsson, Alan Cuthbertson, Dominik Mumberg, Urs B. HagemannList of authors in order
- Landing page
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https://doi.org/10.1136/jitc-2021-002387Publisher landing page
- PDF URL
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https://jitc.bmj.com/content/jitc/9/10/e002387.full.pdfDirect link to full text PDF
- Open access
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YesWhether a free full text is available
- OA status
-
goldOpen access status per OpenAlex
- OA URL
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https://jitc.bmj.com/content/jitc/9/10/e002387.full.pdfDirect OA link when available
- Concepts
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Mesothelin, Cancer research, In vivo, Immune checkpoint, Immune system, Pseudomonas exotoxin, CD8, Medicine, Immunotherapy, In vitro, Biology, Antigen, Immunology, Cytotoxicity, Biochemistry, BiotechnologyTop concepts (fields/topics) attached by OpenAlex
- Cited by
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48Total citation count in OpenAlex
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2025: 16, 2024: 8, 2023: 14, 2022: 10Per-year citation counts (last 5 years)
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43Number of works referenced by this work
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10Other works algorithmically related by OpenAlex
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