Preferentially expressed antigen in melanoma (PRAME) mRNA expression and tumor immune micro-environment (TIME) as prognostic and predictive biomarkers in sarcoma: A Real-world clinicogenomic study

Background
PRAME is an immunogenic cancer-testis antigen and an emerging target for adoptive cellular therapies and other immune-based treatments. While PRAME expression has been described in several sarcoma histologies, its prevalence, immune correlates, and prognostic significance across sarcomas have not been comprehensively evaluated. We leveraged a large real-world clinicogenomic database to characterize PRAME expression across sarcoma subtypes and examine associations with the tumor immune microenvironment and overall survival (OS).

Methods
The Tempus Lens Platform (Tempus AI, Inc., Chicago, IL) was used to query the Tempus multimodal de-identified database for patients (pts) with a diagnosis of sarcoma and both DNA (Tempus xT) and RNA (Tempus xT-R) testing. RNA-seq data were normalized by computing transcripts per million (TPM) for all protein-coding transcripts and then transforming them by log2 (TPM+1). PD-L1 was assessed using the 22C3 clone. Pts were classified by Tempus Immune Profile Score (IPS, low/high) and immune cell infiltration proportions were estimated using quanTIseq. PRAME expression was split into high or low based on the median. Kaplan-Meier curves and CoxPH were used for survival analysis.

Results
5,790 patients were identified. Median age 62, 51% female, 76% Caucasian, 13% African American. Sarcoma subtypes consisted of: 23% GIST, 19% leiomyosarcoma (LMS), 10% liposarcoma (LPS), 9.3% UPS, 6.3% angiosarcoma, 2.6% synovial sarcoma. 50% had stage IV at diagnosis, 41% HLA-A*02:01 positive. Highest levels of PRAME mRNA expression (highest to lowest) were found in synovial sarcoma, angiosarcoma, Ewings, osteosarcoma and LPS. TMB-high (≥ 10), PD-L1 positivity and high IPS score were all positively correlated with PRAME expression. Patients with low PRAME expression were enriched in M1, M2 macrophages, NK cells and T-reg cells compared to patients with high PRAME expression. Median OS was 32.1 and 21.3 months in the low vs. high expressing patients in the general population (p = 3.05 x 10), and GIST drove most of these results, with 79.6 and 45.4 m (low vs. high), p = 0.00017.

Conclusions
In the largest study of PRAME expression in sarcomas to date, PRAME mRNA expression was linked to a significantly worse overall survival as well as an immune-rich microenvironment, especially in GIST and angiosarcoma. This highlights a population which could benefit from emerging PRAME-directed immunotherapies.