Cyclophosphamide Synergizes with Type I Interferons through Systemic Dendritic Cell Reactivation and Induction of Immunogenic Tumor Apoptosis
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Abstract
Successful chemotherapy accounts for both tumor-related factors and host immune response. Compelling evidence suggests that some chemotherapeutic agents can induce an immunogenic type of cell death stimulating tumor-specific immunity. Here, we show that cyclophosphamide (CTX) exerts two types of actions relevant for the induction of antitumor immunity in vivo: (i) effect on dendritic cell (DC) homeostasis, mediated by endogenous type I interferons (IFN-I), leading to the preferential expansion of CD8α+ DC, the main subset involved in the cross-presentation of cell-derived antigens; and (ii) induction of tumor cell death with clear-cut immunogenic features capable of stimulating tumor infiltration, engulfment of tumor apoptotic material, and CD8 T-cell cross-priming by CD8α+ DC. Notably, the antitumor effects of CTX were efficiently amplified by IFN-I, the former providing a source of antigen and a “resetting” of the DC compartment and the latter supplying optimal costimulation for T-cell cross-priming, resulting in the induction of a strong antitumor response and tumor rejection. These results disclose new perspectives for the development of targeted and more effective chemoimmunotherapy treatments of cancer patients. Cancer Res; 71(3); 768–78. ©2010 AACR.
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Some chemotherapies such as cyclophosphamide, gemcitabine, and vinblastine recruited and activated DC in the immunogenic cell death manner.
“Besides suppressor cells, some certain chemotherapies such as cyclophosphamide, gemcitabine, and vinblastine recruited and activated DC in the immunogenic cell death manner [47–49].”
From Combination strategies with PD-1/PD-L1 blockade: current advances and future directions (2022) · cites this paper as [47]
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“So far, anthracyclins (22), bleomycin (23), bortezomib (24), cyclophosphamide (25, 26), daunorubicin (22), doxorubicin (22), idarubicin (22), melphalan (27), oxaliplatin (31), paclitaxel (44) and trifluridine/tipiracil (29) have been proved to induce ICDs; while, cisplatin, mitomycin C were proved to induce non-immuno…”
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- Authors
- Schiavoni, G., Sistigu, A., Valentini, M., Mattei, F., Sestili, P., Spadaro, F., Sanchez, M., Lorenzi, S., D'Urso, M. T., Belardelli, F., Gabriele, L., Proietti, E., & Bracci, L.
- Affiliations
- Istituto Superiore di Sanità (IT)
- Authors' Affiliation: Department of Cell Biology and Neurosciences, Istituto Superiore di Sanità, Rome, Italy
- ORCID
- Venue
- Cancer Research
- Published
- 2011-02-01
- Volume
- 71
- Issue
- 3
- Pages
- 768-778
- ISSN
- 0008-5472 (ISSN-L)
- 1538-7445
- OpenAlex
- W2160423806
- Cited by
- 362
- References
- 49
- Citations by year
- 2026: 9 · 2025: 19 · 2024: 26 · 2023: 28 · 2022: 23 · 2021: 29 · 2020: 32 · 2019: 32 · 2018: 20 · 2017: 21 · 2016: 27 · 2015: 33 · 2014: 17 · 2013: 23 · 2012: 15
- FWCI
- 6.31
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Cancer Research (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › Immunotherapy and Immune Responses
- Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
- Life Sciences › Immunology and Microbiology › Immunology › Immunotoxicology and immune responses
- Keywords
- cyclophosphamide, type I interferon, dendritic cells, CD8α+ dendritic cells, immunogenic cell death, tumor cell apoptosis, cross-presentation, antitumor immunity, chemoimmunotherapy, dendritic cell homeostasis, tumor rejection
- MeSH terms
- Animals, Bone Marrow Cells, Cyclophosphamide, Dendritic Cells, Drug Synergism, Interferon Type I, Lymphoma, Melanoma, Experimental, Thymoma, Apoptosis, CD8-Positive T-Lymphocytes, Mice
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