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)

Background

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.

Methods

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.

Results

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.

Conclusions

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.

Clinical trial identification

Editorial acknowledgement

Legal entity responsible for the study

Caris Life Sciences.

Funding

Has not received any funding.

Disclosure

H. Krause, A. Farrell, A. Elliott: Financial Interests, Personal, Full or part-time Employment: Caris life sciences. W.R. Chen: Financial Interests, Personal, Advisory Role: Immunophotonics. A. Naqash: Financial Interests, Personal, Other, Social Media Editor and Consultant: JCO Precision Oncology; Financial Interests, Institutional, Local PI: Loxo, Surface Oncology, ADC Therapeutics, IGM Biosciences, NiKang Therapeutics, Inspirna, Revolution Medicine, Jacobio, Pionyr, Jazz, NGM; Financial Interests, Institutional, Coordinating PI: EMD Serono, Aravive; Non-Financial Interests, Other, Social Media Consultant and Scientific Committee Member: ASCO; Non-Financial Interests, Other, Educational Activity: OncLive; Non-Financial Interests, Leadership Role, Scientific Committee Co-Chair: Orien; Non-Financial Interests, Leadership Role, Early Career Scientist Committee: SITC. All other authors have declared no conflicts of interest.