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A synergistic triad of chemotherapy, immune checkpoint inhibitors, and caloric restriction mimetics eradicates tumors in mice
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We have recently shown that chemotherapy with immunogenic cell death (ICD)-inducing agents can be advantageously combined with fasting regimens or caloric restriction mimetics (CRMs) to achieve superior tumor growth control via a T cell-dependent mechanism. Here, we show that the blockade of the CD11b-dependent extravasation of myeloid cells blocks such a combination effect as well. Based on the characterization of the myeloid and lymphoid immune infiltrates, including the expression pattern of immune checkpoint proteins (and noting a chemotherapy-induced overexpression of programmed death-ligand 1, PD-L1, on both cancer cells and leukocytes, as well as a reduced frequency of exhausted CD8+ T cells positive for programmed cell death 1 protein, PD-1), we then evaluated the possibility to combine ICD inducers, CRMs and targeting of the PD-1/PD-L1 interaction. While fasting or CRMs failed to improve tumor growth control by PD-1 blockade, ICD inducers alone achieved a partial sensitization to treatment with a PD-1-specific antibody. However, definitive cure of most of the tumor-bearing mice was only achieved by a tritherapy combining (i) ICD inducers exemplified by mitoxantrone and oxaliplatin, (ii) CRMs exemplified by hydroxycitrate and spermidine and substitutable for by fasting, and (iii) immune checkpoint inhibitors (ICIs) targeting the PD-1/PD-L1 interaction. Altogether, these results point to the possibility of synergistic interactions among distinct classes of anticancer agents.
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Polyamines are autophagy inducers implicated in immune regulation and have been shown to improve anti-cancer immunity in mice, synergizing with anti-PD ligand 1 immunotherapy.
“Polyamines are autophagy inducers33 that are implicated in immune regulation and have been shown to improve anti-cancer immunity in mice, synergizing with anti-PD ligand 1 immunotherapy22,34.”
From Longitudinal gut microbiome changes in immune checkpoint blockade-treated advanced melanoma (2024) · cites this paper as [34]
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Metadata
- Authors
- Lévesque, S., Le Naour, J., Pietrocola, F., Paillet, J., Kremer, M., Castoldi, F., Baracco, E. E., Wang, Y., Vacchelli, E., Stoll, G., Jolly, A., De La Grange, P., Zitvogel, L., Kroemer, G., & Pol, J. G.
- Affiliations
- Inserm (FR)
- Gustave Roussy Comprehensive Cancer Institute, Villejuif, France
- GenoSplice Technology, Paris, France
- Université Paris-Sud (FR)
- Karolinska University Hospital (SE)
- Corresponding author
- Zitvogel, Laurence
- Kroemer, Guido
- Pol, Jonathan G.
- ORCID
- Venue
- OncoImmunology
- Publisher
- Informa UK Limited
- Published
- 2019-09-07
- Volume
- 8
- Issue
- 11
- Pages
- e1657375
- ISSN
- 2162-4011 (ISSN-L)
- 2162-402X
- PMC
- PMC6791453
- OpenAlex
- W2971492131
- Cited by
- 86
- References
- 70
- Citations by year
- 2026: 4 · 2025: 4 · 2024: 14 · 2023: 5 · 2022: 23 · 2021: 13 · 2020: 20 · 2019: 3
- FWCI
- 6.17
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- OncoImmunology (publishedVersion, cc-by-nc-nd)
- Europe PMC (PubMed Central) (publishedVersion, cc-by-nc-nd)
- PubMed Central (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- HAL (submittedVersion, other-oa)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- Agence Nationale de la Recherche (ANR-16-ECVD-0008)
- Topics
- Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
- Health Sciences › Medicine › Physiology (medical) › Dietary Effects on Health
- Life Sciences › Immunology and Microbiology › Immunology › Immunotherapy and Immune Responses
- Keywords
- immunogenic cell death, caloric restriction mimetics, immune checkpoint inhibitors, PD-1/PD-L1 blockade, combination chemotherapy, CD11b, tumor immune infiltrate, mitoxantrone, oxaliplatin, hydroxycitrate, spermidine, fasting, tumor growth control
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