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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.
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.
| Original language | English |
|---|---|
| Pages (from-to) | 235-246 |
| Number of pages | 12 |
| Journal | EBioMedicine |
| Volume | 47 |
| Early online date | 25 Aug 2019 |
| DOIs | |
| Publication status | Published - 1 Sept 2019 |
Bibliographical note
Funding Information:The authors thank the patients and parents who contributed samples to the study. Thank you to Victoria Stavrou and Nazia Thakur for assistance with experimental methods. We also thank Paul Stanley and Theresa Morris for technical assistance with electron microscopy. Thank you to Janet Morse, Jane Cooper, Cay Shakespeare, and Sarah-Jane Staveley for consenting of patients and collection of samples for this study. This work was supported by Cancer Research UK , Children's Cancer and Leukaemia Group Little Princess Trust , Treating Children with Cancer, and the alumni and donors to the University of Birmingham . B.N. is funded through the Cancer Research UK Birmingham Centre award.
Publisher Copyright:
© 2019 The Authors
Keywords
- CAR-T
- CD33
- Cancer
- Gemtuzumab
- MDSC
ASJC Scopus subject areas
- Biochemistry, Genetics and Molecular Biology(all)
Access to Document
- Fultang_et_al_MDSC_targeting_with_Gemtuzumab_ozogamicin_restores_T_cell_EBioMedicine_2019_
Fultang, L, Panetti, S, Ng, M, Collins, P, Graef, S, Rizkalla, N, Booth, S, Richard, L, Noyvert, B, Shannon-Lowe, C, Middleton, G, Mussai, F & De Santo, C 2019, 'MDSC targeting with Gemtuzumab ozogamicin restores T cell immunity and immunotherapy against cancers', EBioMedicine, vol. 47, pp. 235-246. https://doi.org/10.1016/j.ebiom.2019.08.025 © 2019 The Authors. Published by Elsevier B.V.
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- 2 Finished
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F Mussai - Clinician Scientist Fellowship: Understanding and targeting the immunosuppressive microenvironment in neuroblastoma
Mussai, F.
1/03/15 → 28/02/21
Project: Research