IL-10 is an immunomodulatory cytokine that is frequently upregulated in various types of cancer. The biological role of IL-10 in cancer is quite complex; however, the presence of IL-10 in advanced metastases and the positive correlation between serum IL-10 levels and progression of disease indicates a critical role of IL-10 in the tumor microenvironment. IL-10 has been shown to directly affect the function of antigen-presenting cells by inhibiting the expression of MHC and costimulatory molecules, which in turn induces immune suppression or tolerance. Additionally, IL-10 downregulates the expression of Th1 cytokines and induces T-regulatory responses. Taken together, a combination of IL-10 antagonism and immunostimulatory treatments such as cancer vaccines, Toll-like receptor agonists, Th1 cytokines, and chemokines would be a logical approach to enhance an antitumor immune response.
Summary Therapy of advanced melanoma has been changing dramatically. Following mutational and biological sub-classification of this heterogeneous cancer, several targeted and immune therapies were approved and increased survival significantly. To facilitate further advancements through pre-clinical in vivo modeling, we have established 459 patient-derived xenografts (PDX) and live tissue samples from 384 patients representing the full spectrum of clinical, therapeutic, mutational, and biological heterogeneity of melanoma. PDX have been characterized using targeted sequencing and protein arrays, and are clinically annotated. This exhaustive live tissue resource includes PDX from 57 samples resistant to targeted therapy, 61 samples from responders and non-responders to immune checkpoint blockade, and 31 samples from brain metastasis. Uveal, mucosal, and acral subtypes are represented as well. We show examples of pre-clinical trials that highlight how the PDX collection can be used to develop and optimize precision therapies, biomarkers of response, and the targeting of rare genetic subgroups.
Uveal melanoma is the most common intraocular tumor in adults and often metastasizes to the liver, leaving patients with few options. Recurrent activating mutations in the G proteins, Gαq and Gα11, are observed in approximately 93% of all uveal melanomas. While therapeutic intervention of downstream Gαq/11 targets has been unsuccessful in treating uveal melanoma, using in vitro [35S]GTPγS binding and cell signaling assays we have found that the Gαq/11 inhibitor, FR900359 (FR), effectively inhibits oncogenic Gαq/11 signaling in uveal melanoma cells expressing either mutant Gαq or Gα11. Inhibition of oncogenic Gαq/11 by FR results in cell cycle arrest and induction of apoptosis. Furthermore, colony formation is prevented by FR treatment of uveal melanoma cells in 3D‐cell culture, providing promise for future in vivo studies. This suggests direct inhibition of activating Gαq/11 mutants may be a potential means of treating uveal melanoma. Support or Funding Information Dr. Ralph and Marian Falk Medical Research Trust and NIH award F31 CA225064 This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
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