Abstract：
:Small molecule based targeted therapies for the treatment of metastatic melanoma hold promise but responses are often not durable, and tumors frequently relapse. Response to adoptive cell transfer (ACT)-based immunotherapy in melanoma patients are durable but patients develop resistance primarily due to loss of antigen expression. The combination of small molecules that sustain T cell effector function with ACT could lead to long lasting responses. Here, we have developed a novel co-culture cell-based high throughput assay system to identify compounds that could potentially synergize or enhance ACT-based immunotherapy of melanoma. A BRAFV600E mutant melanoma cell line, SB-3123p which is resistant to Pmel-1-directed ACT due to low gp100 expression levels was used to develop a homogenous time resolve fluorescence (HTRF), screening assay. This high throughput screening assay quantitates IFNγ released upon recognition of the SB-3123p melanoma cells by Pmel-1 CD8+ T-cells. A focused collection of approximately 500 small molecules targeting a broad range of cellular mechanisms was screened, and four active compounds that increased melanoma antigen expression leading to enhanced IFNγ production were identified and their in vitro activity was validated. These four compounds may provide a basis for enhanced immune recognition and design of novel therapeutic approaches for patients with BRAF mutant melanoma resistant to ACT due to antigen downregulation.
journal_name
Sci Repjournal_title
Scientific reportsauthors
Dextras C,Dashnyam M,Griner LAM,Sundaresan J,Chim B,Yu Z,Vodnala S,Lee CR,Hu X,Southall N,Marugan JJ,Jadhav A,Restifo NP,Acquavella N,Ferrer M,Singh Adoi
10.1038/s41598-020-62369-1subject
Has Abstractpub_date
2020-03-30 00:00:00pages
5688issue
1issn
2045-2322pii
10.1038/s41598-020-62369-1journal_volume
10pub_type
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