Cancer cells from a primary tumor can disseminate to other tissues,
remaining dormant and clinically undetectable for many years. Little is known
about the cues that cause these dormant cells to “awaken,” resume
proliferating and develop into metastases. Studying mouse models, we found that
sustained lung inflammation caused by tobacco smoke exposure or nasal
instillation of lipopolysaccharide converted disseminated, dormant cancer cells
to aggressively growing metastases. Sustained inflammation induced the formation
of neutrophil extracellular traps (NETs), and these were required for awakening
dormant cancer. Mechanistic analysis revealed that two NET-associated proteases,
neutrophil elastase and matrix metalloproteinase 9, sequentially cleaved
laminin. The proteolytically remodeled laminin induced proliferation of dormant
cancer cells by activating integrin alpha-3beta-1 signaling. Antibodies against
NET-remodeled laminin prevented awakening of dormant cells. Therapies aimed at
preventing dormant cell awakening could potentially prolong the survival of
cancer patients.
Targeted delivery of compounds to particular cell subsets can enhance therapeutic index by concentrating their action on the cells of interest. Because attempts to target tumors directly have yielded limited benefit, we instead target endogenous immune cell subsets in the circulation that can migrate actively into tumors. We describe antibody-targeted nanoparticles that bind to CD8+ T cells in the blood, lymphoid tissues, and tumors of mice. PD-1+ T cells are successfully targeted in the circulation and tumor. The delivery of an inhibitor of TGFβ signaling to PD-1-expressing cells extends the survival of tumor-bearing mice, whereas free drugs have no effect at such doses. This modular platform also enables PD-1-targeted delivery of a TLR7/8 agonist to the tumor microenvironment, increasing the proportion of tumor-infiltrating CD8+ T cells and sensitizing tumors to subsequent anti-PD-1. Targeted delivery of immunotherapy to defined subsets of endogenous leukocytes may be superior to administration of free drugs.
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