Journal article
Three steps to breaking immune tolerance to lymphoma: a microparticle approach
Cancer immunology research, Vol.3(4), pp.389-398
04/2015
DOI: 10.1158/2326-6066.CIR-14-0173
PMCID: PMC4390476
PMID: 25627654
Abstract
In situ immunization aims at generating antitumor immune responses through manipulating the tumor microenvironment. On the basis of recent advances in the understanding of antitumor immunity, we designed a three-step approach to in situ immunization to lymphoma: (i) inducing immunogenic tumor cell death with the chemotherapeutic drug doxorubicin. Doxorubicin enhances the expression of "eat-me" signals by dying tumor cells, facilitating their phagocytosis by dendritic cells (DC). Because of the vesicant activity of doxorubicin, microparticles made of biodegradable polymer poly(lactide-co-glycolide) or PLGA can safely deliver doxorubicin intratumorally and are effective vaccine adjuvants, (ii) enhancing T-cell activation using anti-OX40 and (iii) sustaining T-cell responses by checkpoint blockade using anti-CTLA-4. In vitro, doxorubicin microparticles were less cytotoxic to DCs than to B lymphoma cells, did not require internalization by tumor cells, and significantly enhanced phagocytosis of tumor cells by DCs as compared with soluble doxorubicin. In mice, this three-step therapy induced CD4- and CD8-dependent systemic immune responses that enhanced T-cell infiltration into distant tumors, leading to their eradication and significantly improving survival. Our findings demonstrate that systemic antitumor immune responses can be generated locally by three-step therapy and merit further investigation as an immunotherapy for patients with lymphoma.
Details
- Title: Subtitle
- Three steps to breaking immune tolerance to lymphoma: a microparticle approach
- Creators
- Amani Makkouk - Interdisciplinary Graduate Program in Immunology, University of Iowa, Iowa City, IowaVijaya B Joshi - Department of Pharmaceutical Sciences and Experimental Therapeutics, College of Pharmacy, University of Iowa, Iowa City, IowaCaitlin D Lemke - Holden Comprehensive Cancer Center and Department of Internal Medicine, Carver College of Medicine, University of Iowa, Iowa City, IowaAmaraporn Wongrakpanich - Department of Pharmaceutical Sciences and Experimental Therapeutics, College of Pharmacy, University of Iowa, Iowa City, IowaAlicia K Olivier - Department of Pathology, Carver College of Medicine, University of Iowa, Iowa City, IowaSue E Blackwell - Holden Comprehensive Cancer Center and Department of Internal Medicine, Carver College of Medicine, University of Iowa, Iowa City, IowaAliasger K Salem - Department of Pharmaceutical Sciences and Experimental Therapeutics, College of Pharmacy, University of Iowa, Iowa City, Iowa. Holden Comprehensive Cancer Center and Department of Internal Medicine, Carver College of Medicine, University of Iowa, Iowa City, IowaGeorge J Weiner - Interdisciplinary Graduate Program in Immunology, University of Iowa, Iowa City, Iowa. Holden Comprehensive Cancer Center and Department of Internal Medicine, Carver College of Medicine, University of Iowa, Iowa City, Iowa. george-weiner@uiowa.edu
- Resource Type
- Journal article
- Publication Details
- Cancer immunology research, Vol.3(4), pp.389-398
- DOI
- 10.1158/2326-6066.CIR-14-0173
- PMID
- 25627654
- PMCID
- PMC4390476
- NLM abbreviation
- Cancer Immunol Res
- ISSN
- 2326-6066
- eISSN
- 2326-6074
- Publisher
- United States
- Grant note
- P30 ES005605 / NIEHS NIH HHS P50 CA97274/UI / NCI NIH HHS P30 CA086862 / NCI NIH HHS P50 CA097274 / NCI NIH HHS
- Language
- English
- Date published
- 04/2015
- Academic Unit
- Roy J. Carver Department of Biomedical Engineering; Hematology, Oncology, and Blood & Marrow Transplantation; Pharmaceutical Sciences and Experimental Therapeutics; Craniofacial Anomalies Research Center; Dental Research; Chemical and Biochemical Engineering; Holden Comprehensive Cancer Center; Internal Medicine
- Record Identifier
- 9983985958702771
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