415 Mutations in FBXO38, a component of the SCF E3 ubiquitin ligase complex, dampen anti-tumor immunity
Year: 2026
Type: conference-abstract
Abstract: Background While immune checkpoint inhibitors (ICIs) have resulted in significant progress in the treatment of melanoma, patients who do not respond to ICIs are left with limited treatment options. Tumor cell-intrinsic mechanisms are increasingly implicated in ICI resistance, which motivated investigation into recurrent mutations observed in non-responder patients. Leveraging whole-exome sequencing data of patient samples from an ICI clinical trial, we identified that mutations in FBXO38, a component of the SCF E3 ubiquitin ligase complex, selectively occurred in non-responders. To investigate mechanistic effects of FBXO38 deficiency, we generated FBXO38 knock-out melanoma cell lines for in vivo anti-tumor immunity studies.Methods FBXO38 was deleted via CRISPR/Cas9 in B16.SIY melanoma cells. Tumor growth was evaluated in C57BL/6 mice. Dependency on CD8 + T cells was evaluated through anti-CD8b antibody depletion. Composition of infiltrating immune cells was assessed through flow cytometry.Results Genetic ablation of FBXO38 resulted in significantly increased tumor growth compared to WT B16.SIY cells in vivo. When CD8+ T cells were ablated, KO and control tumors grew at similar rates, indicating an immune-dependent mechanism for this difference. Flow cytometry of immune cells in FBXO38 KO tumors revealed similar levels of CD8+ T cells, including SIY antigen-specific CD8+ T cells, compared to control tumors. However, FBXO38 KO tumors had significantly increased B cell infiltration. Additionally, PD-1+ CD4+ T cell populations were markedly increased in KO tumors. The biological mechanism for this increased B cell and CD4+ T cell infiltrate, and how it impairs immune-mediated tumor control, are currently under investigation.Conclusions FBXO38 deficiency in melanoma results in significantly increased tumor growth in vivo. The phenotype of FBXO38 KO tumors is immune-dependent and likely is a consequence of increased B cell infiltration into the tumor microenvironment. These studies warrant investigation into the biochemical effects of FBXO38 in tumor cells that regulate host immunity, in search of novel therapeutic strategies.
Authors: Stephen C Barrett, Thomas F Gajewski
Institution: University of Chicago
Language: English
Subfield: Oncology
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $2,490
OpenAlex ID: W7225137560