How would you summarize your study for a lay audience? Immune checkpoint inhibitors are cancer fighting drugs that help the immune system do its job of detecting and attacking tumor cells. Programmed Cell Death 1 (PD-1) is a common target for this type of drug-;it is a protein that sits on the surface of T cells and helps regulate the immune system's response to neighboring cells, both normal and cancerous. While most research efforts to date have focused on PD-1's role in T cells, it is also active in many other kinds of cells-;including cancer cells as first demonstrated by the Schatton laboratory.
We aimed to define the molecular mechanisms controlling PD-1 expression and its therapeutic targeting in melanoma cells. Our team identified a melanoma cell-intrinsic type I interferon-JAK/STAT signaling circuit regulating the amount of PD-1 in tumor cells. We further discovered that inhibition of this pathway not only reversed induction of PD-1 on melanoma cells, but also reduced the efficacy of PD-1 checkpoint therapy.
Our work thus cautions against combining JAK or IFNAR antagonists with PD-1 inhibitors, given that this regimen may weaken the effectiveness of immune checkpoint monotherapy. What knowledge gaps does your study help to fill? This work builds off our previously published studies identifying PD-1 as a tumor cell-intrinsic growth promoting receptor in melanoma and Merkel cell carcinoma, the inhibition of which suppresses cancer progression. Here, we newly define a r.