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Interferon gene therapy reprograms the leukemia microenvironment inducing protective immunity to multiple tumor antigens
- Source :
- Nature Communications, Vol 9, Iss 1, Pp 1-16 (2018), Nature Communications
- Publication Year :
- 2018
- Publisher :
- Nature Portfolio, 2018.
-
Abstract
- Immunotherapy is emerging as a new pillar of cancer treatment with potential to cure. However, many patients still fail to respond to these therapies. Among the underlying factors, an immunosuppressive tumor microenvironment (TME) plays a major role. Here we show that monocyte-mediated gene delivery of IFNα inhibits leukemia in a mouse model. IFN gene therapy counteracts leukemia-induced expansion of immunosuppressive myeloid cells and imposes an immunostimulatory program to the TME, as shown by bulk and single-cell transcriptome analyses. This reprogramming promotes T-cell priming and effector function against multiple surrogate tumor-specific antigens, inhibiting leukemia growth in our experimental model. Durable responses are observed in a fraction of mice and are further increased combining gene therapy with checkpoint blockers. Furthermore, IFN gene therapy strongly enhances anti-tumor activity of adoptively transferred T cells engineered with tumor-specific TCR or CAR, overcoming suppressive signals in the leukemia TME. These findings warrant further investigations on the potential development of our gene therapy strategy towards clinical testing.<br />An immune suppressive tumor microenvironment (TME) is a limitation for immunotherapy. Here the authors show that, in a B cell acute lymphoblastic leukemia mouse model, gene-based delivery of IFNα reprograms the leukemia-induced immunosuppressive TME into immunostimulatory and enhances T-cell responses.
- Subjects :
- 0301 basic medicine
Male
Genetic enhancement
medicine.medical_treatment
T-Lymphocytes
General Physics and Astronomy
Immunotherapy, Adoptive
0302 clinical medicine
Interferon
hemic and lymphatic diseases
Tumor Microenvironment
lcsh:Science
Cells, Cultured
Regulation of gene expression
Multidisciplinary
Gene Expression Regulation, Leukemic
Precursor Cell Lymphoblastic Leukemia-Lymphoma
3. Good health
Leukemia
030220 oncology & carcinogenesis
Female
medicine.drug
Transgene
Science
Mice, Transgenic
Gene delivery
General Biochemistry, Genetics and Molecular Biology
Article
03 medical and health sciences
Antigens, Neoplasm
Cell Line, Tumor
medicine
Animals
Tumor microenvironment
business.industry
Animal
Immunity
General Chemistry
Immunotherapy
Genetic Therapy
medicine.disease
Mice, Inbred C57BL
030104 developmental biology
T-Lymphocyte
Cancer research
lcsh:Q
Interferons
sense organs
business
Subjects
Details
- Language :
- English
- ISSN :
- 20411723
- Volume :
- 9
- Issue :
- 1
- Database :
- OpenAIRE
- Journal :
- Nature Communications
- Accession number :
- edsair.doi.dedup.....9b0f288dbf23ef1148f63d56ecb93f13