Science Spotlight

The hidden function of anti-tumoral drug Motolimod to target immunosuppressive cells

from Dr. Nora Disis, Clinical Research Division
Monocytic myeloid derived suppressor cells (mMDSC) express higher levels of TLR8 mRNA. Motolimod treatment induces cell death of mMDSC in both normal donors and cancer patients. Pre-treatment of PBMC with FAS neutralizing antibody inhibits the cell death of mMDSC.
Monocytic myeloid derived suppressor cells (mMDSC) express higher levels of TLR8 mRNA. Motolimod treatment induces cell death of mMDSC in both normal donors and cancer patients. Pre-treatment of PBMC with FAS neutralizing antibody inhibits the cell death of mMDSC. Figure provided by Dr. Dang.

Myeloid-derived suppressor cells, or MDSC, is a heterogeneous population of cells. In healthy individuals, MDSC differentiate into granulocytes, monocytes or dendritic cells, critical components of an efficient immune response. However, in cancer patients MDSC are maintained in an undifferentiated state and characterized by their ability to suppress the immune response, predominantly directed against T lymphocytes. Such immunosuppressive properties represent a block in mounting an anti-tumoral immune response and also hamper efficient therapeutic interventions. Few therapeutics targeting MDSC are available.

Motolimod, also called VTX2337, an experimental drug agonist of Toll Like Receptor 8 (TLR8) was demonstrated to target and eradicate MDSC, in a study from Dr. Nora Disis (Clinical Research Division and UW) along with Drs. Yushe Dang and Zina Rutnam (Cancer Vaccine Institute at UW). The results of this study were recently published in the Journal of Leukocyte Biology.

As explained by Dr. Dang, “Motolimod activates mDC (dendritic cells) and monocytes to produce IL-12 and TNFa, which increase Th1 immune responses by activated T cells”. Indeed, Motolimod was already known as an activator of myeloid cells such as dendritic or natural killer cells through TLR8 pathway activation. Since MDSC also belong to the myeloid cell lineage, the expression of TLR8 in these cells was analyzed to determine whether they could also be a target of Motolimod.

Peripheral blood samples were obtained from cancer patients (melanoma, prostate, colon cancers) or healthy volunteers, and the cells of interest were isolated by flow cytometry to quantify TLR8 mRNA expression. MDSC expressed greater levels of TLR8 relative to dendritic cells. Additionally, among the two subsets composing MDSC (granulocytic or monocytic) only monocytic MDSC (mMDSC) expressed TLR8.  mMDSC are responsible for T cell inactivation.

Motolimod led to a significant reduction of MDSC among peripheral blood mononuclear cells (PBMC) in vitro. Treatment of PBMC with 167 nanomolar or 500 nanomolar of Motolimod decreased the presence of mMDSC by 50% and 80%, respectively. This was true for cells from both healthy volunteers and cancer patients. mMDSC decrease was not observed with other agonists of either TLR7 and TLR9, but was observed with CL075, a drug targeting both TLR7 and TLR8.

This reduction in MDSC was explained by an increased apoptotic cell death in the presence of Motolimod. Said Dr. Dang, “treatment with Motolimod indirectly activate T cells by the cytokines secreted by mDC and monocytes. FAS ligand expression is upregulated on the activated T cells. Fas positive MDSC among PBMC are susceptible to FAS mediated killing by activated T cells.” Indeed, Motolimod induced Fas Ligand expression on both CD4+ and CD8+ T cells and the addition of a Fas blocking receptor inhibited T-cell mediated MSDC apoptosis. This reduction in MDSC allowed partial restoration of T cell activation as observed by IL2 secretion upon exposure of the T cells to CD3/CD28 stimuli.

Collectively, these data demonstrate that Motolimod restores T cell activation by allowing T cell-mediated killing of the immunosuppressive MDSC. More studies like this are necessary to identify new ways to target immunosuppressive cells in cancer patients. Motolimod is especially promising as it targets several types of myeloid cells in favor of an anti-tumoral immune response. Such a drug could be used prior to or in combination with anti-tumoral therapy to optimize the treatment outcomes. When asked about the future implications of this study, Dr. Dang concluded, “We are excited that Motolimod is a clinical grade drug and has been shown to be safe to give to patients with cancer.  Understanding the multiple ways in which the drug can modulate the immune system will allow us to use the agent as part of a combination approach to enhance T-cell activation.”

 

This study was funded by grants from VentiRX Pharmaceutical, Komen Leadership and the Athena Distinguished Professorship for Breast Cancer Research.

 

Research reported in the publication is a collaboration between Cancer Consortium members Nora Disis (Fred Hutch and UW) and Hailing Lu (previously UW).

 

Dang Y,Rutnam ZJ,Dietsch G,Lu H,Yang Y,Hershberg R,Disis ML. 2018. TLR8 ligation induces apoptosis of monocytic myeloid-derived suppressor cells. Journal of Leukocyte Biology. 103(1), 157-164.

 

Science Spotlight Editors
From the left: Science Spotlight editors Yiting Lim (Basic Sciences), Kyle Woodward (Clinical Research), Nicolas Chuvin (Human Biology), Maggie Burhans (Public Health Sciences) and Brianna Traxinger (Vaccine and Infectious Disease) Photo by Robert Hood / Fred Hutch

EDITORS

Yiting Lim
Basic Sciences Division

Nicolas Chuvin
Human Biology Division

Maggie Burhans, Ph.D.
Public Health Sciences Division

Brianna Traxinger
Vaccine and Infectious Disease Division

Kyle Woodward
Clinical Research Division

Julian Simon, Ph.D.
Faculty Mentor
Clinical Research Division
and Human Biology Division

Allysha Eyler
Publication Tracking
Arnold Digital Library

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