Type I IFNs promote cancer cell stemness by triggering the epigenetic regulator KDM1B.


Journal

Nature immunology
ISSN: 1529-2916
Titre abrégé: Nat Immunol
Pays: United States
ID NLM: 100941354

Informations de publication

Date de publication:
09 2022
Historique:
received: 18 04 2021
accepted: 17 07 2022
pubmed: 25 8 2022
medline: 20 9 2022
entrez: 24 8 2022
Statut: ppublish

Résumé

Cancer stem cells (CSCs) are a subpopulation of cancer cells endowed with high tumorigenic, chemoresistant and metastatic potential. Nongenetic mechanisms of acquired resistance are increasingly being discovered, but molecular insights into the evolutionary process of CSCs are limited. Here, we show that type I interferons (IFNs-I) function as molecular hubs of resistance during immunogenic chemotherapy, triggering the epigenetic regulator demethylase 1B (KDM1B) to promote an adaptive, yet reversible, transcriptional rewiring of cancer cells towards stemness and immune escape. Accordingly, KDM1B inhibition prevents the appearance of IFN-I-induced CSCs, both in vitro and in vivo. Notably, IFN-I-induced CSCs are heterogeneous in terms of multidrug resistance, plasticity, invasiveness and immunogenicity. Moreover, in breast cancer (BC) patients receiving anthracycline-based chemotherapy, KDM1B positively correlated with CSC signatures. Our study identifies an IFN-I → KDM1B axis as a potent engine of cancer cell reprogramming, supporting KDM1B targeting as an attractive adjunctive to immunogenic drugs to prevent CSC expansion and increase the long-term benefit of therapy.

Identifiants

pubmed: 36002648
doi: 10.1038/s41590-022-01290-3
pii: 10.1038/s41590-022-01290-3
pmc: PMC9477743
doi:

Substances chimiques

Anthracyclines 0
Interferon Type I 0
Histone Demethylases EC 1.14.11.-

Types de publication

Journal Article

Langues

eng

Sous-ensembles de citation

IM

Pagination

1379-1392

Commentaires et corrections

Type : CommentIn
Type : CommentIn

Informations de copyright

© 2022. The Author(s).

Références

Dean, M., Fojo, T. & Bates, S. Tumour stem cells and drug resistance. Nat. Rev. Cancer 5, 275–284 (2005).
pubmed: 15803154 doi: 10.1038/nrc1590
Batlle, E. & Clevers, H. Cancer stem cells revisited. Nat. Med. 23, 1124–1134 (2017).
pubmed: 28985214 doi: 10.1038/nm.4409
Vitale, I., Shema, E., Loi, S. & Galluzzi, L. Intratumoral heterogeneity in cancer progression and response to immunotherapy. Nat. Med. 27, 212–224 (2021).
pubmed: 33574607 doi: 10.1038/s41591-021-01233-9
Cao, J. & Yan, Q. Cancer epigenetics, tumor immunity, and immunotherapy. Trends Cancer 6, 580–592 (2020).
pubmed: 32610068 pmcid: 7330177 doi: 10.1016/j.trecan.2020.02.003
Wainwright, E. N. & Scaffidi, P. Epigenetics and cancer stem cells: unleashing, hijacking, and restricting cellular plasticity. Trends Cancer 3, 372–386 (2017).
pubmed: 28718414 pmcid: 5506260 doi: 10.1016/j.trecan.2017.04.004
Cheng, Y. et al. Targeting epigenetic regulators for cancer therapy: mechanisms and advances in clinical trials. Signal Transduct. Target. Ther. 4, 62 (2019).
pubmed: 31871779 pmcid: 6915746 doi: 10.1038/s41392-019-0095-0
Dawson, M. A. & Kouzarides, T. Cancer epigenetics: from mechanism to therapy. Cell 150, 12–27 (2012).
pubmed: 22770212 doi: 10.1016/j.cell.2012.06.013
Topper, M. J., Vaz, M., Marrone, K. A., Brahmer, J. R. & Baylin, S. B. The emerging role of epigenetic therapeutics in immuno-oncology. Nat. Rev. Clin. Oncol. 17, 75–90 (2020).
pubmed: 31548600 doi: 10.1038/s41571-019-0266-5
Villanueva, L., Alvarez-Errico, D. & Esteller, M. The contribution of epigenetics to cancer immunotherapy. Trends Immunol. 41, 676–691 (2020).
pubmed: 32622854 doi: 10.1016/j.it.2020.06.002
Schiavoni, G. et al. Cyclophosphamide synergizes with type I interferons through systemic dendritic cell reactivation and induction of immunogenic tumor apoptosis. Cancer Res. 71, 768–778 (2011).
pubmed: 21156650 doi: 10.1158/0008-5472.CAN-10-2788
Sistigu, A. et al. Cancer cell-autonomous contribution of type I interferon signaling to the efficacy of chemotherapy. Nat. Med. 20, 1301–1309 (2014).
pubmed: 25344738 doi: 10.1038/nm.3708
Kroemer, G., Galassi, C., Zitvogel, L. & Galluzzi, L. Immunogenic cell stress and death. Nat. Immunol. 23, 487–500 (2022).
pubmed: 35145297 doi: 10.1038/s41590-022-01132-2
Galluzzi, L. et al. Molecular mechanisms of cell death: recommendations of the Nomenclature Committee on Cell Death 2018. Cell Death Differ. 25, 486–541 (2018).
pubmed: 29362479 pmcid: 5864239 doi: 10.1038/s41418-017-0012-4
Musella, M., Manic, G., De Maria, R., Vitale, I. & Sistigu, A. Type-I-interferons in infection and cancer: unanticipated dynamics with therapeutic implications. Oncoimmunology 6, e1314424 (2017).
pubmed: 28638743 pmcid: 5467995 doi: 10.1080/2162402X.2017.1314424
Hugo, W. et al. Genomic and transcriptomic features of response to Anti-PD-1 therapy in metastatic melanoma. Cell 165, 35–44 (2016).
pubmed: 26997480 pmcid: 4808437 doi: 10.1016/j.cell.2016.02.065
Benci, J. L. et al. Opposing functions of interferon coordinate adaptive and innate immune responses to cancer immune checkpoint blockade. Cell 178, 933–948 e914 (2019).
pubmed: 31398344 pmcid: 6830508 doi: 10.1016/j.cell.2019.07.019
Lee, J. et al. Activation of innate immunity is required for efficient nuclear reprogramming. Cell 151, 547–558 (2012).
pubmed: 23101625 pmcid: 3506423 doi: 10.1016/j.cell.2012.09.034
Fang, R. et al. Human LSD2/KDM1b/AOF1 regulates gene transcription by modulating intragenic H3K4me2 methylation. Mol. Cell 39, 222–233 (2010).
pubmed: 20670891 pmcid: 3518444 doi: 10.1016/j.molcel.2010.07.008
Al-Hajj, M., Wicha, M. S., Benito-Hernandez, A., Morrison, S. J. & Clarke, M. F. Prospective identification of tumorigenic breast cancer cells. Proc. Natl Acad. Sci. USA 100, 3983–3988 (2003).
pubmed: 12629218 pmcid: 153034 doi: 10.1073/pnas.0530291100
Bocci, F. et al. Toward understanding cancer stem cell heterogeneity in the tumor microenvironment. Proc. Natl Acad. Sci. USA 116, 148–157 (2019).
pubmed: 30587589 doi: 10.1073/pnas.1815345116
Marine, J. C., Dawson, S. J. & Dawson, M. A. Non-genetic mechanisms of therapeutic resistance in cancer. Nat. Rev. Cancer 20, 743–756 (2020).
pubmed: 33033407 doi: 10.1038/s41568-020-00302-4
Balkwill, F. Cancer and the chemokine network. Nat. Rev. Cancer 4, 540–550 (2004).
pubmed: 15229479 doi: 10.1038/nrc1388
Acharyya, S. et al. A CXCL1 paracrine network links cancer chemoresistance and metastasis. Cell 150, 165–178 (2012).
pubmed: 22770218 pmcid: 3528019 doi: 10.1016/j.cell.2012.04.042
Wiedemann, G. M. et al. Cancer cell-derived IL-1alpha induces CCL22 and the recruitment of regulatory T cells. Oncoimmunology 5, e1175794 (2016).
pubmed: 27757295 pmcid: 5048775 doi: 10.1080/2162402X.2016.1175794
Vacchelli, E. et al. Chemotherapy-induced antitumor immunity requires formyl peptide receptor 1. Science 350, 972–978 (2015).
pubmed: 26516201 doi: 10.1126/science.aad0779
Lucarini, V. et al. Combining Type I Interferons and 5-Aza-2’-Deoxycitidine to Improve Anti-Tumor Response against Melanoma. J. Invest Dermatol 137, 159–169 (2017).
pubmed: 27623509 doi: 10.1016/j.jid.2016.08.024
Dixon, G. et al. QSER1 protects DNA methylation valleys from de novo methylation. Science 372, eabd0875 (2021).
Lu, H. et al. Chemotherapy-induced S100A10 recruits KDM6A to facilitate OCT4-mediated breast cancer stemness. J. Clin. Investig. 130, 4607–4623 (2020).
pubmed: 32427586 pmcid: 7456215 doi: 10.1172/JCI138577
Zhang, W. et al. Targeting KDM4A epigenetically activates tumor-cell-intrinsic immunity by inducing DNA replication stress. Mol. Cell 81, 2148–2165.e9 (2021).
Hollern, D. P. et al. B Cells and T follicular helper cells mediate response to checkpoint inhibitors in high mutation burden mouse models of breast cancer. Cell 179, 1191–1206 e1121 (2019).
pubmed: 31730857 pmcid: 6911685 doi: 10.1016/j.cell.2019.10.028
Shats, I. et al. Using a stem cell-based signature to guide therapeutic selection in cancer. Cancer Res. 71, 1772–1780 (2011).
pubmed: 21169407 doi: 10.1158/0008-5472.CAN-10-1735
Palmer, N. P., Schmid, P. R., Berger, B. & Kohane, I. S. A gene expression profile of stem cell pluripotentiality and differentiation is conserved across diverse solid and hematopoietic cancers. Genome Biol. 13, R71 (2012).
pubmed: 22909066 pmcid: 3491371 doi: 10.1186/gb-2012-13-8-r71
Rodriguez-Ruiz, M. E. et al. Apoptotic caspases inhibit abscopal responses to radiation and identify a new prognostic biomarker for breast cancer patients. Oncoimmunology 8, e1655964 (2019).
pubmed: 31646105 pmcid: 6791460 doi: 10.1080/2162402X.2019.1655964
Weichselbaum, R. R. et al. An interferon-related gene signature for DNA damage resistance is a predictive marker for chemotherapy and radiation for breast cancer. Proc. Natl Acad. Sci. USA 105, 18490–18495 (2008).
pubmed: 19001271 pmcid: 2587578 doi: 10.1073/pnas.0809242105
Barrat, F. J., Crow, M. K. & Ivashkiv, L. B. Interferon target-gene expression and epigenomic signatures in health and disease. Nat. Immunol. 20, 1574–1583 (2019).
pubmed: 31745335 pmcid: 7024546 doi: 10.1038/s41590-019-0466-2
Park, S. H. et al. Type I interferons and the cytokine TNF cooperatively reprogram the macrophage epigenome to promote inflammatory activation. Nat. Immunol. 18, 1104–1116 (2017).
pubmed: 28825701 pmcid: 5605457 doi: 10.1038/ni.3818
Zitvogel, L., Galluzzi, L., Kepp, O., Smyth, M. J. & Kroemer, G. Type I interferons in anticancer immunity. Nat. Rev. Immunol. 15, 405–414 (2015).
pubmed: 26027717 doi: 10.1038/nri3845
Bracci, L., Sistigu, A., Proietti, E. & Moschella, F. The added value of type I interferons to cytotoxic treatments of cancer. Cytokine Growth Factor Rev. 36, 89–97 (2017).
pubmed: 28693974 doi: 10.1016/j.cytogfr.2017.06.008
Doherty, M. R. et al. Interferon-beta represses cancer stem cell properties in triple-negative breast cancer. Proc. Natl Acad. Sci USA 114, 13792–13797 (2017).
pubmed: 29229854 pmcid: 5748193 doi: 10.1073/pnas.1713728114
Castiello, L. et al. Disruption of IFN-I signaling promotes HER2/Neu tumor progression and breast cancer stem cells. Cancer Immunol. Res 6, 658–670 (2018).
pubmed: 29622580 doi: 10.1158/2326-6066.CIR-17-0675
Zhu, Y. et al. Influence of interferon-alpha on the expression of the cancer stem cell markers in pancreatic carcinoma cells. Exp. Cell. Res. 324, 146–156 (2014).
pubmed: 24726912 doi: 10.1016/j.yexcr.2014.03.020
Qadir, A. S. et al. CD95/Fas increases stemness in cancer cells by inducing a STAT1-dependent Type I interferon response. Cell Rep. 18, 2373–2386 (2017).
pubmed: 28273453 pmcid: 5474321 doi: 10.1016/j.celrep.2017.02.037
Li, S. et al. Interferon alpha-inducible protein 27 promotes epithelial-mesenchymal transition and induces ovarian tumorigenicity and stemness. J. Surg. Res. 193, 255–264 (2015).
pubmed: 25103640 doi: 10.1016/j.jss.2014.06.055
Meacham, C. E. & Morrison, S. J. Tumour heterogeneity and cancer cell plasticity. Nature 501, 328–337 (2013).
pubmed: 24048065 pmcid: 4521623 doi: 10.1038/nature12624
Turajlic, S., Sottoriva, A., Graham, T. & Swanton, C. Resolving genetic heterogeneity in cancer. Nat. Rev. Genet. 20, 404–416 (2019).
pubmed: 30918367 doi: 10.1038/s41576-019-0114-6
Maccalli, C., Volonte, A., Cimminiello, C. & Parmiani, G. Immunology of cancer stem cells in solid tumours. A review. Eur. J. Cancer 50, 649–655 (2014).
pubmed: 24333096 doi: 10.1016/j.ejca.2013.11.014
Miao, Y. et al. Adaptive immune resistance emerges from tumor-initiating stem cells. Cell 177, 1172–1186 e1114 (2019).
pubmed: 31031009 pmcid: 6525024 doi: 10.1016/j.cell.2019.03.025
Jacquelot, N. et al. Sustained Type I interferon signaling as a mechanism of resistance to PD-1 blockade. Cell Res. 29, 846–861 (2019).
Chen, J. et al. Type I IFN protects cancer cells from CD8+ T cell-mediated cytotoxicity after radiation. J. Clin. Investig. 129, 4224–4238 (2019).
pubmed: 31483286 pmcid: 6763250 doi: 10.1172/JCI127458
Fan, J.B. et al. Type I interferon regulates a coordinated gene network to enhance cytotoxic T cell-mediated tumor killing. Cancer Discov. 10, 382–393 (2020).
Keklikoglou, I. et al. Chemotherapy elicits pro-metastatic extracellular vesicles in breast cancer models. Nat. Cell Biol. 21, 190–202 (2019).
pubmed: 30598531 doi: 10.1038/s41556-018-0256-3
Wu, X. et al. Intrinsic immunity shapes viral resistance of stem cells. Cell 172, 423–438 e425 (2018).
pubmed: 29249360 doi: 10.1016/j.cell.2017.11.018
Sheng, W. et al. LSD1 ablation stimulates anti-tumor immunity and enables checkpoint blockade. Cell 174, 549–563 e519 (2018).
pubmed: 29937226 pmcid: 6063761 doi: 10.1016/j.cell.2018.05.052
Qin, Y. et al. Inhibition of histone lysine-specific demethylase 1 elicits breast tumor immunity and enhances antitumor efficacy of immune checkpoint blockade. Oncogene 38, 390–405 (2019).
pubmed: 30111819 doi: 10.1038/s41388-018-0451-5
Wu, L. et al. KDM5 histone demethylases repress immune response via suppression of STING. PLoS Biol. 16, e2006134 (2018).
pubmed: 30080846 pmcid: 6095604 doi: 10.1371/journal.pbio.2006134
Topper, M. J. et al. Epigenetic therapy ties MYC depletion to reversing immune evasion and treating lung cancer. Cell 171, 1284–1300 e1221 (2017).
pubmed: 29195073 pmcid: 5808406 doi: 10.1016/j.cell.2017.10.022
Manic, G. et al. CHK1-targeted therapy to deplete DNA replication-stressed, p53-deficient, hyperdiploid colorectal cancer stem cells. Gut 67, 903–917 (2018).
pubmed: 28389531 doi: 10.1136/gutjnl-2016-312623
Golebiewska, A., Brons, N. H., Bjerkvig, R. & Niclou, S. P. Critical appraisal of the side population assay in stem cell and cancer stem cell research. Cell Stem Cell 8, 136–147 (2011).
pubmed: 21295271 doi: 10.1016/j.stem.2011.01.007
Lorenzi, S. et al. Type I IFNs control antigen retention and survival of CD8alpha(+) dendritic cells after uptake of tumor apoptotic cells leading to cross-priming. J. Immunol. 186, 5142–5150 (2011).
pubmed: 21441457 doi: 10.4049/jimmunol.1004163
Corces, M. R. et al. An improved ATAC-seq protocol reduces background and enables interrogation of frozen tissues. Nat. Methods 14, 959–962 (2017).
pubmed: 28846090 pmcid: 5623106 doi: 10.1038/nmeth.4396
Bruno, T. et al. Che-1/AATF-induced transcriptionally active chromatin promotes cell proliferation in multiple myeloma. Blood Adv. 4, 5616–5630 (2020).
pubmed: 33186461 pmcid: 7686885 doi: 10.1182/bloodadvances.2020002566
Ewels, P. A. et al. The nf-core framework for community-curated bioinformatics pipelines. Nat. Biotechnol. 38, 276–278 (2020).
pubmed: 32055031 doi: 10.1038/s41587-020-0439-x
Hu, Y. & Smyth, G. K. ELDA: extreme limiting dilution analysis for comparing depleted and enriched populations in stem cell and other assays. J. Immunol. Methods 347, 70–78 (2009).
pubmed: 19567251 doi: 10.1016/j.jim.2009.06.008
Hanzelmann, S., Castelo, R. & Guinney, J. GSVA: gene set variation analysis for microarray and RNA-seq data. BMC Bioinf. 14, 7 (2013).
doi: 10.1186/1471-2105-14-7

Auteurs

Martina Musella (M)

Dipartimento di Medicina e Chirurgia Traslazionale, Università Cattolica del Sacro Cuore, Rome, Italy.

Andrea Guarracino (A)

Department of Biology, University of Rome 'Tor Vergata', Rome, Italy.
Genomics Research Centre, Human Technopole, Milan, Italy.

Nicoletta Manduca (N)

Dipartimento di Medicina e Chirurgia Traslazionale, Università Cattolica del Sacro Cuore, Rome, Italy.

Claudia Galassi (C)

Dipartimento di Medicina e Chirurgia Traslazionale, Università Cattolica del Sacro Cuore, Rome, Italy.
Department of Radiation Oncology, Weill Cornell Medical College, New York, NY, USA.

Eliana Ruggiero (E)

Experimental Hematology Unit, IRCCS San Raffaele Scientific Institute, Milan, Italy.

Alessia Potenza (A)

Experimental Hematology Unit, IRCCS San Raffaele Scientific Institute, Milan, Italy.

Ester Maccafeo (E)

Dipartimento di Medicina e Chirurgia Traslazionale, Università Cattolica del Sacro Cuore, Rome, Italy.

Gwenola Manic (G)

Italian Institute for Genomic Medicine (IIGM), Candiolo, Italy.
Candiolo Cancer Institute, FPO - IRCCS, Candiolo, Italy.

Luca Mattiello (L)

Italian Institute for Genomic Medicine (IIGM), Candiolo, Italy.
Candiolo Cancer Institute, FPO - IRCCS, Candiolo, Italy.

Sara Soliman Abdel Rehim (S)

Department of Biology, University of Rome 'Tor Vergata', Rome, Italy.
Italian Institute for Genomic Medicine (IIGM), Candiolo, Italy.

Michele Signore (M)

RPPA Unit, Proteomics Area, Core Facilities, Istituto Superiore di Sanità, Rome, Italy.

Marco Pietrosanto (M)

Department of Biology, University of Rome 'Tor Vergata', Rome, Italy.

Manuela Helmer-Citterich (M)

Department of Biology, University of Rome 'Tor Vergata', Rome, Italy.

Matteo Pallocca (M)

UOSD Clinical Trial Center, Biostatistics and Bioinformatics, IRCCS Regina Elena National Cancer Institute, Rome, Italy.

Maurizio Fanciulli (M)

SAFU Unit, IRCCS Regina Elena National Cancer Institute, Rome, Italy.

Tiziana Bruno (T)

SAFU Unit, IRCCS Regina Elena National Cancer Institute, Rome, Italy.

Francesca De Nicola (F)

SAFU Unit, IRCCS Regina Elena National Cancer Institute, Rome, Italy.

Giacomo Corleone (G)

SAFU Unit, IRCCS Regina Elena National Cancer Institute, Rome, Italy.

Anna Di Benedetto (A)

Pathology Unit, IRCCS Regina Elena National Cancer Institute, Rome, Italy.

Cristiana Ercolani (C)

Pathology Unit, IRCCS Regina Elena National Cancer Institute, Rome, Italy.

Edoardo Pescarmona (E)

Pathology Unit, IRCCS Regina Elena National Cancer Institute, Rome, Italy.

Laura Pizzuti (L)

Division of Medical Oncology 2, IRCCS Regina Elena National Cancer Institute, Rome, Italy.

Francesco Guidi (F)

Dipartimento di Medicina e Chirurgia Traslazionale, Università Cattolica del Sacro Cuore, Rome, Italy.
Fondazione Policlinico Universitario 'A. Gemelli' - IRCCS, Rome, Italy.

Francesca Sperati (F)

UOSD Clinical Trial Center, Biostatistics and Bioinformatics, IRCCS San Gallicano Dermatological Institute, Rome, Italy.

Sara Vitale (S)

Dipartimento di Medicina e Chirurgia Traslazionale, Università Cattolica del Sacro Cuore, Rome, Italy.

Daniele Macchia (D)

Center of Animal Research and Welfare, Istituto Superiore di Sanità, Rome, Italy.

Massimo Spada (M)

Center of Animal Research and Welfare, Istituto Superiore di Sanità, Rome, Italy.

Giovanna Schiavoni (G)

Department of Oncology and Molecular Medicine, Istituto Superiore di Sanità, Rome, Italy.

Fabrizio Mattei (F)

Department of Oncology and Molecular Medicine, Istituto Superiore di Sanità, Rome, Italy.

Adele De Ninno (A)

Institute for Photonics and Nanotechnologies, Italian National Research Council, Rome, Italy.

Luca Businaro (L)

Institute for Photonics and Nanotechnologies, Italian National Research Council, Rome, Italy.

Valeria Lucarini (V)

Department of Paediatric Haematology/Oncology and of Cell and Gene Therapy, Ospedale Pediatrico Bambino Gesù, IRCCS, Rome, Italy.

Laura Bracci (L)

Department of Oncology and Molecular Medicine, Istituto Superiore di Sanità, Rome, Italy.

Eleonora Aricò (E)

FaBioCell, Core Facilities, Istituto Superiore di Sanità, Rome, Italy.

Giovanna Ziccheddu (G)

Oncogenomics and Epigenetics, IRCCS Regina Elena National Cancer Institute, Rome, Italy.

Francesco Facchiano (F)

Department of Oncology and Molecular Medicine, Istituto Superiore di Sanità, Rome, Italy.

Stefania Rossi (S)

Department of Oncology and Molecular Medicine, Istituto Superiore di Sanità, Rome, Italy.

Massimo Sanchez (M)

Cytometry Unit, Core Facilities, Istituto Superiore di Sanità, Rome, Italy.

Alessandra Boe (A)

Cytometry Unit, Core Facilities, Istituto Superiore di Sanità, Rome, Italy.

Mauro Biffoni (M)

Department of Oncology and Molecular Medicine, Istituto Superiore di Sanità, Rome, Italy.

Ruggero De Maria (R)

Dipartimento di Medicina e Chirurgia Traslazionale, Università Cattolica del Sacro Cuore, Rome, Italy. ruggero.demaria@unicatt.it.
Fondazione Policlinico Universitario 'A. Gemelli' - IRCCS, Rome, Italy. ruggero.demaria@unicatt.it.

Ilio Vitale (I)

Italian Institute for Genomic Medicine (IIGM), Candiolo, Italy. ilio.vitale@gmail.com.
Candiolo Cancer Institute, FPO - IRCCS, Candiolo, Italy. ilio.vitale@gmail.com.

Antonella Sistigu (A)

Dipartimento di Medicina e Chirurgia Traslazionale, Università Cattolica del Sacro Cuore, Rome, Italy. antonella.sistigu@unicatt.it.
Fondazione Policlinico Universitario 'A. Gemelli' - IRCCS, Rome, Italy. antonella.sistigu@unicatt.it.
Tumor Immunology and Immunotherapy Unit, IRCCS Regina Elena National Cancer Institute, Rome, Italy. antonella.sistigu@unicatt.it.

Articles similaires

[Redispensing of expensive oral anticancer medicines: a practical application].

Lisanne N van Merendonk, Kübra Akgöl, Bastiaan Nuijen
1.00
Humans Antineoplastic Agents Administration, Oral Drug Costs Counterfeit Drugs

Smoking Cessation and Incident Cardiovascular Disease.

Jun Hwan Cho, Seung Yong Shin, Hoseob Kim et al.
1.00
Humans Male Smoking Cessation Cardiovascular Diseases Female
Humans United States Aged Cross-Sectional Studies Medicare Part C
1.00
Humans Yoga Low Back Pain Female Male

Classifications MeSH