Data from Adding Indoximod to Hypofractionated Radiotherapy with Anti-PD-1 Checkpoint Blockade Enhances Early NK and CD8<sup>+</sup> T-Cell–Dependent Tumor Activity Article Swipe
Tsubasa Watanabe
,
Simone Gaedicke
,
Elena Guffart
,
Elke Firat
,
Gabriele Niedermann
·
YOU?
·
· 2023
· Open Access
·
· DOI: https://doi.org/10.1158/1078-0432.c.6528587
YOU?
·
· 2023
· Open Access
·
· DOI: https://doi.org/10.1158/1078-0432.c.6528587
Purpose:There is growing interest in combinations of immunogenic radiotherapy (RT) and immune checkpoint blockade, but clinical responses are still limited. Therefore, we tested the triple therapy with an inhibitor of the indoleamine 2,3-dioxygenase pathway, which like immune checkpoints, downregulates the antitumor immune response.Experimental Design:Triple treatment with hypofractionated RT (hRT) + anti-PD-1 antibody (αPD1) + indoximod was compared with the respective mono- and dual therapies in two syngeneic mouse models.Results:The tumors did not regress following treatment with hRT + αPD1. The αPD1/indoximod combination was not effective at all. In contrast, triple treatment induced rapid, marked tumor regression, even in mice with a large tumor. The effects strongly depended on CD8+ T cells and partly on natural killer (NK) cells. Numbers and functionality of tumor-specific CD8+ T cells and NK cells were increased, particularly early during treatment. However, after 2.5–3 weeks, all large tumors relapsed, which was accompanied by increased apoptosis of tumor-infiltrating lymphocytes associated with a non-reprogrammable state of exhaustion, terminal differentiation, and increased activation-induced cell death, which could not be prevented by indoximod in these aggressive tumor models. Some mice with a smaller tumor were cured. Reirradiation during late regression (day 12), but not after relapse, cured almost all mice with a large B16-CD133 tumor, and strongly delayed relapse in the less immunogenic 4T1 model, depending on CD8+ T cells.Conclusions:Our findings may serve as a rationale for the clinical evaluation of this triple-combination therapy in patients with solitary or oligometastatic tumors in the neoadjuvant or the definitive setting.
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- Type
- preprint
- Language
- en
- Landing Page
- https://doi.org/10.1158/1078-0432.c.6528587
- OA Status
- gold
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- 10
- OpenAlex ID
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https://openalex.org/W4361947025Canonical identifier for this work in OpenAlex
- DOI
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https://doi.org/10.1158/1078-0432.c.6528587Digital Object Identifier
- Title
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Data from Adding Indoximod to Hypofractionated Radiotherapy with Anti-PD-1 Checkpoint Blockade Enhances Early NK and CD8<sup>+</sup> T-Cell–Dependent Tumor ActivityWork title
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preprintOpenAlex work type
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enPrimary language
- Publication year
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2023Year of publication
- Publication date
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2023-03-31Full publication date if available
- Authors
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Tsubasa Watanabe, Simone Gaedicke, Elena Guffart, Elke Firat, Gabriele NiedermannList of authors in order
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https://doi.org/10.1158/1078-0432.c.6528587Publisher landing page
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YesWhether a free full text is available
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goldOpen access status per OpenAlex
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https://doi.org/10.1158/1078-0432.c.6528587Direct OA link when available
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CD8, Blockade, Cancer research, Immune system, Apoptosis, Immune checkpoint, Antibody, Immunotherapy, Medicine, Biology, Internal medicine, Immunology, Receptor, BiochemistryTop concepts (fields/topics) attached by OpenAlex
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0Total citation count in OpenAlex
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10Other works algorithmically related by OpenAlex
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| abstract_inverted_index.radiotherapy | 8 |
| abstract_inverted_index.Reirradiation | 186 |
| abstract_inverted_index.downregulates | 38 |
| abstract_inverted_index.functionality | 120 |
| abstract_inverted_index.tumor-specific | 122 |
| abstract_inverted_index.2,3-dioxygenase | 32 |
| abstract_inverted_index.oligometastatic | 239 |
| abstract_inverted_index.αPD1/indoximod | 80 |
| abstract_inverted_index.differentiation, | 160 |
| abstract_inverted_index.hypofractionated | 46 |
| abstract_inverted_index.activation-induced | 163 |
| abstract_inverted_index.non-reprogrammable | 155 |
| abstract_inverted_index.triple-combination | 232 |
| abstract_inverted_index.tumor-infiltrating | 150 |
| abstract_inverted_index.Design:<p>Triple | 43 |
| abstract_inverted_index.CD8<sup>+</sup> | 108, 123, 217 |
| abstract_inverted_index.setting.</p></div> | 247 |
| abstract_inverted_index.response.</p>Experimental | 42 |
| abstract_inverted_index.models.</p>Results:<p>The | 68 |
| abstract_inverted_index.cells.</p>Conclusions:<p>Our | 219 |
| abstract_inverted_index.<div>AbstractPurpose:<p>There | 0 |
| cited_by_percentile_year | |
| countries_distinct_count | 0 |
| institutions_distinct_count | 5 |
| sustainable_development_goals[0].id | https://metadata.un.org/sdg/3 |
| sustainable_development_goals[0].score | 0.7900000214576721 |
| sustainable_development_goals[0].display_name | Good health and well-being |
| citation_normalized_percentile.value | 0.17472616 |
| citation_normalized_percentile.is_in_top_1_percent | False |
| citation_normalized_percentile.is_in_top_10_percent | False |