MDSC targeting with Gemtuzumab ozogamicin restores T cell immunity and immunotherapy against cancers

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 CART 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-CART 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 CART cell responses against multiple cancers. In the rare conditions of HLH/MAS gemtuzumab ozogamicin provides a novel antimyeloid strategy.

Myeloid-derived suppressor cells—new and exciting players in lung cancer

“…The argeting of MDSCs with GO leads to GO internalization, increased p-ATM, and MDSC cell death. Anti-GD2-/mesothelin-/EGFRvIII-CAR-T cell activity is enhanced in combination with the anti-MDSC effects of GO [138]. This research suggests that, for patients with high levels of MDSCs, immune "cold" tumors may be transferred into immune "hot" tumors via GO therapy to improve the efficacy of chemotherapeutic and/or immunotherapeutic regimens.…”

Plasticity in Pro- and Anti-tumor Activity of Neutrophils: Shifting the Balance

“…The immunotoxin Gemtuzumab ozogamicin was used to deplete cells expressing CD33, identified as a surface marker on suppressive cells across cancer types. This depletion restored T cell proliferation, enhanced CAR T cell responses and tumor cell death ( 180 ).…”

Chronic Staphylococcus aureus infection is cured by theory-driven therapy

“…In fact, targeting MDSCs 34;35 and boosting the immune system 32 have been shown to favour bacterial reduction but nonetheless failed to induce sterilizing immunity in chronically infected individuals. However, although MDSC-depletion seems to be beneficial in diseases such as cancer 36;37 , in bacterial infections such treatment would simultaneously deplete important monocytes and by extension, dendritic cells and macrophages 38 .…”