MDSC targeting with Gemtuzumab ozogamicin restores T cell immunity and immunotherapy against cancersResearch in Context

MDSC targeting with Gemtuzumab ozogamicin restores T cell immunity and immunotherapy against cancersResearch in Context

Blog Article

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 Advanced Wound Care - Impregnated Dressings 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 Full Comforter Set 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.

Keywords: MDSC, Gemtuzumab, CD33, Cancer, CAR-T.