How would you summarize your examine for a lay viewers?
Immune checkpoint inhibitors are most cancers combating medication that assist the immune system do its job of detecting and attacking tumor cells. Programmed Cell Demise 1 (PD-1) is a standard goal for any such drug-;it’s a protein that sits on the floor of T cells and helps regulate the immune system’s response to neighboring cells, each regular and cancerous. Whereas most analysis efforts to this point have targeted on PD-1’s function in T cells, additionally it is energetic in lots of different kinds of cells-;together with most cancers cells as first demonstrated by the Schatton laboratory.
We aimed to outline the molecular mechanisms controlling PD-1 expression and its therapeutic focusing on in melanoma cells. Our group recognized a melanoma cell-intrinsic kind I interferon-JAK/STAT signaling circuit regulating the quantity of PD-1 in tumor cells. We additional found that inhibition of this pathway not solely reversed induction of PD-1 on melanoma cells, but in addition decreased the efficacy of PD-1 checkpoint remedy. Our work thus cautions in opposition to combining JAK or IFNAR antagonists with PD-1 inhibitors, provided that this routine might weaken the effectiveness of immune checkpoint monotherapy.
What information gaps does your examine assist to fill?
This work builds off our beforehand printed research figuring out PD-1 as a tumor cell-intrinsic development selling receptor in melanoma and Merkel cell carcinoma, the inhibition of which suppresses most cancers development. Right here, we newly outline a regulatory pathway controlling PD-1 ranges on melanoma cells and the way inhibition of this pathway unintentionally disrupts therapeutic efficacy of immune checkpoint blockade. We are able to use these findings to optimize immunotherapeutic responses for sufferers with melanoma, and probably even different most cancers sorts.
How did you conduct your examine?
To know the mechanisms that govern PD-1 checkpoint expression in melanoma cells, we targeted on established cytokine networks recognized to control PD-1 in immune cells. We hypothesized that these mediators would have the same function in modulating melanoma cell-PD-1 ranges. Via our work, we found {that a} kind I interferon cytokine pathway intrinsic to melanoma cells critically controls tumor cell-PD-1 expression. We additionally discovered that disruption of kind I interferon signaling reduces melanoma-PD-1 expression and resultant efficacy of immune checkpoint remedy.
What are the implications?
Kind I interferon antagonists, together with JAK inhibitors and IFNAR1 antibodies, presently prescribed within the clinic for a number of autoimmune circumstances comparable to psoriasis, atopic dermatitis, vitiligo and lupus might probably suppress efficacy of PD-1 immune checkpoint remedy. Our work thus raises concern over utilizing PD-1 checkpoint antibodies (e.g. nivolumab or pembrolizumab) with JAK inhibitors (e.g. ruxolitinib, utabacitinib, deucravacitinib) or IFNAR1 antibodies (e.g. anifrolumab).
What are the following steps?
Subsequent steps embody dissecting roles of kind I interferon signaling and inhibition not solely on melanoma cell-PD-1 expression, focusing on, and checkpoint efficacy, but in addition in extra most cancers sorts in addition to in numerous immune and non-immune cell lineages throughout the tumor microenvironment. Figuring out extra regulatory networks controlling tumor cell-PD-1 expression and their results on immunotherapeutic outcomes are additionally main thrusts of our ongoing analysis. Our general aim is to leverage these findings to enhance immune checkpoint therapeutic responses in most cancers sufferers.
Authorship: Along with Drs. Schatton and Barthel, different BWH authors embody Julia Holzgruber, Christina Martins, Zsofi Kulcsar, Alexandra Duplaine, Erik Rasbach, Laure Migayron, Praveen Singh, Edith Statham, and Matthew R. Ramsey. Further non-BWH authors embody Jennifer Landsberg, Katia Boniface, Julien Seneschal, Wolfram Hoetzenecker, Emma Berdan and Shannah Ho Sui.
Funding: This work was assist by a Analysis Grant from the Dermatology Basis, Milstein Analysis Scholar Award from the American Pores and skin Affiliation, Fund to Maintain Analysis Excellence from the Brigham Analysis Institute at Brigham and Girls’s Hospital and NIH/NCI grants (R01CA190838, R01CA247957 and R01CA258637). Partial assist was offered by a Developmental Undertaking Grant from the Harvard Stem Cell Institute, Klaus-Wolff Fellowships from the Austrian Society of Dermatology and Venereology, Marietta Blau-Grant from Austria’s Company for Training and Internationalisation, Analysis Fellowship from the European Academy of Dermatology and Venereology, and a Walter Benjamin Scholarship from the German Analysis Basis.
Supply:
Brigham and Girls’s Hospital
Journal reference:
Holzgruber, J., et al. (2024). Kind I interferon signaling induces melanoma cell-intrinsic PD-1 and its inhibition antagonizes immune checkpoint blockade. Nature Communications. doi.org/10.1038/s41467-024-51496-2.
