Immune checkpoint inhibitors are cancer-fighting drugs that help the immune system do its job of detecting and attacking tumour 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 neighbouring 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 tumour cells.
We further discovered that inhibition of this pathway not only reversed the 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.
This work builds off our previously published studies identifying PD-1 as a tumour cell-intrinsic growth-promoting receptor in melanoma and Merkel cell carcinoma, the inhibition of which suppresses cancer progression.
Here, we newly define a regulatory pathway controlling PD-1 levels in melanoma cells and how inhibition of this pathway unintentionally disrupts the therapeutic efficacy of immune checkpoint blockade.
We can use these findings to optimise immunotherapeutic responses for patients with melanoma, and potentially even other cancer types.
To understand the mechanisms that govern PD-1 checkpoint expression in melanoma cells, we focused on established cytokine networks known to regulate PD-1 in immune cells.
We hypothesised that these mediators would have a similar role in modulating melanoma cell-PD-1 levels.
Through our work, we discovered that a type I interferon cytokine pathway intrinsic to melanoma cells critically controls tumour cell-PD-1 expression.
We also found that disruption of type I interferon signaling reduces melanoma-PD-1 expression and the resultant efficacy of immune checkpoint therapy.
Type I interferon antagonists, including JAK inhibitors and IFNAR1 antibodies, currently prescribed in the clinic for multiple autoimmune conditions such as psoriasis, atopic dermatitis, vitiligo, and lupus may potentially suppress the efficacy of PD-1 immune checkpoint therapy.
Our work thus raises concern over using PD-1 checkpoint antibodies (e.g. nivolumab or pembrolizumab) with JAK inhibitors (e.g. ruxolitinib, utabacitinib, deucravacitinib) or IFNAR1 antibodies (e.g. anifrolumab).
The next steps include dissecting the roles of type I interferon signalling and inhibition not only on melanoma cell-PD-1 expression, targeting, and checkpoint efficacy but also in additional cancer types as well as in diverse immune and non-immune cell lineages within the tumour microenvironment.
Identifying additional regulatory networks controlling tumour cell-PD-1 expression and their effects on immunotherapeutic outcomes are also major thrusts of our ongoing research.
Our overall goal is to leverage these findings to improve immune checkpoint therapeutic responses in cancer patients.
Source: Brigham and Women’s Hospital
