2281P Multi-omics evaluation of TFE3-fusions and potential association with immuno-metabolic vulnerabilities in alveolar soft part sarcoma (ASPS) and translocation-positive renal cell carcinoma (tRCC)

ASPS and tRCC are rare tumors that harbor recurrent fusions of the TFE3 gene; emerging data for both entities suggest responsiveness to immune checkpoint inhibitors (ICIs). We hypothesized that TFE3 fusions drive unique immune-metabolic changes in both entities compared to their non-TFE3-based counterparts. 31 TFE3-rearranged tumors (24 tRCC; 7 ASPS) as well as ccRCC (N =391), undifferentiated pleomorphic sarcoma (N = 111), liposarcoma (N = 49), and angiosarcoma (AS, N = 167) underwent next-generation sequencing (592-gene or whole exome) and whole transcriptome sequencing at Caris Life Sciences (Phoenix, AZ). PD-L1 expression (SP142; +: ≥2+, ≥5%) was tested by IHC. Cellular composition of the tumor immune microenvironment (TIME) was estimated by quanTIseq. A transcriptomic signature predictive of ICI response (interferon γ score) was applied. Differentially regulated pathways were assessed by gene set enrichment analysis (GSEA). p-values adjusted for multiple comparisons. ASPSCR1::TFE3 was the most frequent fusion type (N = 9 [ASPS, N = 7;tRCC, N = 2]). PD-L1+ was more frequent in tRCC vs. ccRCC (46% vs. 12%, p < .05). tRCC had significantly fewer M1 macrophages (0.32-fold, p < 0.05) and lower IFN γ score than ccRCC (-0.31 vs -0.13 Arbitrary Units (AU), p < .05). Of the 9 tRCC fusions with N≥2, PRCC::TFE3 (-0.16 AU) had the highest and SFPQ::TFE3 (-0.52) had the lowest IFN γ score. No difference in PD-L1+ was observed between ASPS (14.5%), AS (23%), LPS (8.5%) or UPS (36%), p > .05. ASPS had a higher median CD8+ T cell infiltrate (1.63%) vs. UPS: 0, LPS: 0 [p > 0.05 both], and AS: 0, p < 0.05. There was no significant difference in IFN γ score between ASPS (-0.30 AU) vs. AS (-0.29), LPS (-0.34), UPS (-0.26), p > .05. GSEA revealed enrichment of the oxidative phosphorylation genes in both tRCC and ASPS vs. appropriate controls. TFE3-rearranged ASPS and tRCC demonstrate a distinct TIME with variable enrichment of immune markers vs. control groups. Further functional studies are warranted to determine whether TFE3-fusions have a role in driving oxidative phosphorylation in ASPS and tRCC.