Metastasis is the primary cause of melanoma death. A major problem with the vast majority of previous studies is that young mice (8-weeks old, equivalent to 20 human years) are used to investigate the mechanisms of metastatic outgrowth, whereas the median age of melanoma diagnosis in humans is ~65 years. Advanced age also correlates with metastasis, mortality, and immune dysfunction. Moreover, most studies often only focus on lung metastases, despite melanoma commonly metastasizing to sites such as the liver in patients, which are significantly more resistant to checkpoint inhibitors (ICIs) compared to patients with lung metastases.
We have begun addressing these core limitations by developing novel syngeneic mouse models of melanoma metastasis and colonization in young (8-week), middle-aged (12-month), and geriatric (18-22 month) mice, in which metastatic colonization/dissemination can be targeted to either the lung or liver alone, or to both sites simultaneously.
Our data now show that aging promotes reactivation of dormant tumor cells and subsequent outgrowth of lung and liver metastases. We have found that frontline innate lymphocytes such as NK-cells and γδ T-cells are decreased in the pre-metastatic lung and livers of aged mice relative to young mice and remain decreased during early and late-stage metastasis. Using inducible KO mouse models and antibody depletion methods in young growth restrictive mice, we find that depletion of either NK-cells or γδ T-cells is sufficient to promote reactivation from dormancy and resistance to anti-PD1 therapy.
Secondly, we further delineated changes in the post-metastatic lung and liver niche. We find that PROS1 secretion by reactivated melanoma cells expressing high levels of the MER tyrosine kinase receptor (MER) in the aged metastatic lung and liver increases two unique myeloid populations: CD11b cells expressing the immunosuppressive factor ARG1 and polymorphonuclear myeloid derived suppressor cells (PMN MDSCs). Treatment with recombinant ARG1 promotes reactivation from dormancy in young mice whilst depletion of PMN MDSCs inhibits age induced outgrowth in the lung and liver.
Overall, our study highlights common immune-mediated age-related changes in the pre and post metastatic lung and liver which contribute to aggressive metastatic initiation, reactivation from dormancy, progression, and resistance to anti-PD1.