EX VIVO LIVE IMAGING OF THE LUNG METASTATIC NICHE ENABLES IMMUNO-ONCOLOGY DRUG DISCOVERY: INHIBITION OF MMP9 PROMOTES CD8+ T CELLS INFILTRATION AND ACTIVATION (MW10)
Vicki Plaks, PhD from Dr. Zena Werb lab (University of California San Francisco, San Francisco, CA, USA) described the use of ex vivo live imaging to visualize the dynamic and spatial interactions between tumor cells and their surrounding stroma cells within lung metastatic niche. Solid tumors commonly metastasize to the lungs, where the use of intravital imaging is a challenge. In contrast, ex vivo live imaging provides the information of ongoing interactions between tumor cells and their surrounding stroma cells in the microenvironment within the resected lung for hours. This imaging technique helped to identify that Gr1+ myeloid cells around lung metastasis are positive for matrix metalloproteinase 9 (MMP9). MMP9 plays multiple roles in tumorigenesis processes, such as angiogenesis, regulation of inflammation, and development of metastatic niche by degrading extracellular matrix. In MMTV-PyMT and VO-PyMT breast cancer models, activated MMP9 was abundant in the primary tumor and lung metastatic sites. Furthermore, data analyses of breast cancer patients identified elevated levels of MMP9, but not MMP2, in metastatic sites. A unique antibody against the catalytic domain of MMP9, called SDS3, targeted lung metastasis and inhibited MMP9 enzymatic activity, leading to reduced lung metastasis with minimal effect on primary tumor in mice. Inhibition of active MMP9 also attenuated colony formation, migration and matrix invasion of metastatic cells while enhanced the infiltration and activation of CD8+ T cells, including PD-1+ T cells. Currently, the assessment of SDS3 in combination with immune checkpoint inhibitors is in progress. Together, targeting extracellular matrix modulators (e.g. MMP9) may be able to expand efficacy of cancer immunotherapy in the lung metastatic niche.
Glossary
MMP = matrix metalloproteinase
PD-1 = programmed cell death protein-1