PD-1 Plays A Key Role in Melanoma Cells and Their Host Immune System Response

Programmed cell death 1 (PD-1) is the primary cancer drug target for immune checkpoint blockade (ICB). Since PD-1 receptor inhibition activates tumor-specific T cell immunity, researchers have mainly focused on the expression of PD-1 on T cells and its immunobiological characteristics. In contrast, researchers currently do not know what the mechanism behind the functional regulation of PD-1 in cancer cells is.

Recently, in a research report titled "Type I interferon signaling induces melanoma cell-intrinsic PD-1 and its inhibition antagonizes immune checkpoint blockade" published in the international journal Nature Communications, scientists from Brigham and Women's Hospital and other institutions in the United States have deeply revealed the key role played by PD-1 in the immune response of melanoma cells and their host body through research.

Immune checkpoint inhibitors are anticancer drugs that help the immune system detect and attack tumor cells. PD-1 is the most common target of this type of drug. It is also a special protein located on the surface of T cells that helps regulate the immune system's response to nearby cells (including normal cells and cancer cells). While most studies to date have focused on revealing the key role of PD-1 in T cells, this is the first time that researchers have shown that it is active in many types of cells, including cancer cells.

Figure 1. Type I interferons promote chromatin opening and STAT-IRF transcription factor binding to a PD-1 gene enhancer in melanoma cells. (Holzgruber J, et al., 2024)

In the article, the researchers aimed to determine the molecular mechanisms that control PD-1 expression and its therapeutic targets in melanoma cells. They identified a specific pathway that helps regulate PD-1 levels in tumor cells, namely the type I interferon-JAK/STAT signaling pathway intrinsic to melanoma cells. After further investigation, the researchers found that inhibiting this pathway not only reversed the induction of PD-1 in melanoma cells, but also reduced the efficacy of PD-1 checkpoint therapy. Therefore, in this study, the researchers reminded that it is necessary to use JAK or IFNAR antagonists in combination with PD-1 inhibitors, because this system may weaken the effectiveness of immune checkpoint monotherapy. Previously, researchers identified PD-1 as a tumor cell-intrinsic growth-promoting receptor in melanoma and Merkel cell carcinoma, and inhibiting PD-1 may inhibit the progression of cancer. Here, the researchers defined a specific regulatory pathway that controls PD-1 levels in melanoma cells and revealed how inhibiting this pathway inadvertently undermines the therapeutic effects of immune checkpoint blockade. These findings may be used to optimize the response to immunotherapy received by melanoma patients, and thus may also be used to treat other cancer types.

To understand the mechanisms behind the control of PD-1 checkpoint expression in melanoma cells, the researchers focused on the established cytokine network known to regulate PD-1 in immune cells. They speculated that these mediators may play a similar role in regulating PD-1 levels in melanoma cells. The study found that the type I interferon cytokine pathway inherent to melanoma cells can strictly control the expression of PD-1 in tumor cells, and that disrupting type I interferon signaling may reduce PD-1 expression in melanoma and thus reduce the efficacy of immune checkpoint therapy. Type I interferon antagonists, including JAK inhibitors and IFNAR1 antibodies, are currently used clinically to treat a variety of autoimmune diseases, including psoriasis, atopic dermatitis, vitiligo, and lupus, and may potentially inhibit the therapeutic efficacy of PD-1 immune checkpoint therapy. The study raises concerns about combining PD-1 checkpoint antibodies (such as nivolumab or pembrolizumab) with JAK inhibitors (such as ruxolitinib, utabacitinib, and deuterated lecitinib) or IFNAR1 antibodies (such as anirumab).

Next, the researchers will further dissect the role of type I interferon signaling and inhibition, not only in melanoma cell PD-1 expression, targeting, and checkpoint efficacy, but also in other cancer types and multiple immune and non-immune cell lines in the tumor microenvironment. Identifying additional regulatory networks that control tumor cell PD-1 expression and their impact on immunotherapy outcomes is an ongoing focus of research, with the overall goal of using these findings to improve immune checkpoint therapy responses in cancer patients. Taken together, these findings reveal a regulatory mechanism of cancer cell PD-1 by type I interferons and provide new mechanistic insights into the potential neutralization of immune checkpoint blockade by widely used IFNAR1 and JAK inhibitors.

Immune Checkpoint Stable Cell Line List

Reference

Holzgruber J, et al. Type I interferon signaling induces melanoma cell-intrinsic PD-1 and its inhibition antagonizes immune checkpoint blockade. Nature Communications, 2024, 15(1): 7165.