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MDSC targeting with Gemtuzumab ozogamicin restores T cell immunity and immunotherapy against cancers
- Source :
- EBIOMEDICINE, EBioMedicine
- Publication Year :
- 2019
- Publisher :
- Elsevier BV, 2019.
-
Abstract
- Background: Targeting of MDSCs is a major clinical challenge in the era of immunotherapy. Antibodies which deplete MDSCs in murine models can reactivate T cell responses. In humans such approaches have not developed due to difficulties in identifying targets amenable to clinical translation. Methods: RNA-sequencing of M-MDSCs and G-MDSCs from cancer patients was undertaken. Flow cytometry and immunohistochemistry of blood and tumours determined MDSC CD33 expression. MDSCs were treated with Gemtuzumab ozogamicin and internalisation kinetics, and cell death mechanisms determined by flow cytometry, confocal microscopy and electron microscopy. Effects on T cell proliferation and CAR-T cell anti-tumour cytotoxicity were identified in the presence of Gemtuzumab ozogamicin. Findings: RNA-sequencing of human M-MDSCs and G-MDSCs identified transcriptomic differences, but that CD33 is a common surface marker. Flow cytometry indicated CD33 expression is higher on M-MDSCs, and CD33+ MDSCs are found in the blood and tumours regardless of cancer subtype. Treatment of human MDSCs leads to Gemtuzumab ozogamicin internalisation, increased p-ATM, and cell death; restoring T cell proliferation. Anti-GD2-/mesothelin-/EGFRvIII-CAR-T cell activity is enhanced in combination with the anti-MDSC effects of Gemtuzumab ozogamicin. Interpretation: The study identifies that M-MDSCs and G-MDSCs are transcriptomically different but CD33 is a therapeutic target on peripheral and infiltrating MDSCs across cancer subtypes. The immunotoxin Gemtuzumab ozogamicin can deplete MDSCs providing a translational approach to reactivate T cell and CAR-T cell responses against multiple cancers. In the rare conditions of HLH/MAS gemtuzumab ozogamicin provides a novel anti-myeloid strategy. Fund: This work was supported by Cancer Research UK, CCLG, Treating Children with Cancer, and the alumni and donors to the University of Birmingham. (c) 2019 The Authors. Published by Elsevier B.V. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
- Subjects :
- 0301 basic medicine
Research paper
Gemtuzumab ozogamicin
T-Lymphocytes
medicine.medical_treatment
T cell
MDSC
Cell
CD33
Models, Biological
General Biochemistry, Genetics and Molecular Biology
Immunophenotyping
Flow cytometry
03 medical and health sciences
Antineoplastic Agents, Immunological
0302 clinical medicine
Immunotoxin
Neoplasms
Medicine and Health Sciences
medicine
Humans
Cancer
medicine.diagnostic_test
business.industry
Gene Expression Profiling
Myeloid-Derived Suppressor Cells
Biology and Life Sciences
General Medicine
Immunotherapy
medicine.disease
Immunohistochemistry
Gemtuzumab
CAR-T
030104 developmental biology
medicine.anatomical_structure
030220 oncology & carcinogenesis
Cancer research
Transcriptome
business
Biomarkers
medicine.drug
Subjects
Details
- ISSN :
- 23523964
- Volume :
- 47
- Database :
- OpenAIRE
- Journal :
- EBioMedicine
- Accession number :
- edsair.doi.dedup.....90c818af8a8891ec1135d25fcbff890c