Abstract 2060: Independent validation of endogenous retrotransposable elements as predictive biomarkers of immune checkpoint blockade response

Résumé fourni par la source

Abstract Background: Endogenous retrotransposable elements (EREs) can modulate antitumor immune responses via viral mimicry response. We previously described an association between ERE upregulation and radiological response to immune checkpoint blockade (ICB) in advanced solid tumors in the phase II INSPIRE trial (NCT02644369) (ASCO 2024). Here, we validate the association of EREs and ICB response in two independent cohorts of patients (pts) with melanoma and non-small cell lung cancer (NSCLC) treated with ICB. Methods: Publicly available datasets were screened to identify cohorts of pts with solid tumors receiving ICB with accessible clinical outcomes (responders, RP; or non-responders, NR) and total RNA-sequencing data. Two independent datasets (Riaz et al., PMID 29033130; Jung et al., PMID 31537801) were examined. ERE expression was analyzed in total RNA-seq from anonymized raw data in baseline (B) and on-treatment (T) samples of pts with melanoma and B samples of NSCLC. Differentially expressed EREs between RP and NR were quantified by the TPMscore (mean of normalized transcript per million values for upregulated EREs in a sample comparison) and its standardized Zscore. Immune cell infiltration was inferred from RNA-seq-based deconvolution. The cytolytic activity (CYT) immune score, derived from the mRNA expression of GZMA and PRF1, was reported in the melanoma cohort, while tumor mutational burden (TMB) data was available for both cohorts. Results: A total of 43 pts (14 RP and 29 NR) in the melanoma cohort and 27 pts (8 RP and 19 NR) in the NSCLC cohort were identified for analysis. Baseline upregulated ERE classes included LINE (27%), SINE (30%), LTR (23%), simple repeats (10%), and others (10%) in melanoma, and LINE (34%), SINE (21%), LTR (29%), simple repeats (8%), and others (8%) in NSCLC. Differential ERE expression was observed in RP compared to NR across B samples in both cohorts (melanoma: RP vs NR Zscore 0.50 vs -0.23, p< 0.001; NSCLC: RP vs NR Zscore 0.89 vs -0.27, p= 0.001). In the melanoma cohort, on-treatment samples confirmed higher ERE expression in RP vs NR (Zscore 0.77 vs -0.32, p< 0.001). A moderate positive correlation between TPMscore of RP and CD8+ T cell expression vs NR was seen in the melanoma pts in B samples (Pearson correlation R = 0.54, p = 0.001) and on-treatment (R= 0.62, p< 0.001), but no correlation was seen in B samples of the NSCLC cohort (R= 0.2, p= 0.31). Zscore did not correlate with TMB in melanoma or NSCLC pts. In melanoma pts, the Zscore showed a moderate positive correlation with CYT immune score (R= 0.41, p= 0.017). Conclusion: This validation study on melanoma and NSCLC pts adds to the previously observed association of ERE upregulation and clinical outcomes during ICB treatment in a pan-cancer cohort. The association with CD8+ T cell infiltration and CYT immune score, but not with TMB, suggests an immune activation independent of other biomarkers such as TMB. Citation Format: Mercedes Herrera, Sajid A. Marhon, Farnoosh Abbas-Aghababazadeh, David Chen, Amy Liu, Helen LooYau, Emily Van de Laar, Jeffrey Bruce, Helen Chow, Philippe L. Bedard, Albiruni Razak, Anna Spreafico, Aaron R. Hansen, Marcus O. Butler, Stephanie Lheureux, Trevor J. Pugh, Benjamin Haibe-Kains, Daniel D. De Carvalho, Lillian L. Siu, Pavlina Spiliopoulou. Independent validation of endogenous retrotransposable elements as predictive biomarkers of immune checkpoint blockade response [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 2060.

Ce résumé expose les affirmations des auteurs. BNTIC ne l’interprète pas comme une validation indépendante des résultats.