Work

The DDR-immune fitness score: a biomarker for guiding parp and immunotherapy synergy in extensive-stage small cell lung cancer

Year: 2025

Type: article

Abstract: Background Despite the integration of PD-L1 inhibitors with chemotherapy, extensive-stage small-cell lung cancer (ES-SCLC) continues to portend a dismal prognosis, with a 5-year survival rate below 10%. A critical unmet need is the lack of validated biomarkers to identify patients who may benefit from novel combinations of DNA damage repair (DDR) inhibitors and immune checkpoint blockers (ICB). Methods We developed a novel three-variable biomarker, the DDR-Immune Fitness (DDR-IF) score, by integrating data from a systematic review of six phase II trials (PRISMA-2020) with single-cell transcriptomic data from 82 SCLC tumors. The score, constructed using elastic-net regression, incorporates homologous recombination deficiency (HRD), tumor mutational burden (TMB), and STING pathway activity. Its predictive performance was validated in an independent cohort from the MSK-IMPACT study (n=152 ES-SCLC patients receiving PARP-ICB). Results DDR-IF-high tumors were characterized by a distinct biological profile, including (i) transcriptional exhaustion of the cGAS-STING innate immune pathway (p < 0.001), (ii) significantly reduced CD8 + T cell infiltration (2.3-fold fewer, p = 0.004), and (iii) a superior pooled objective response rate to PARP-ICB combinations (42% vs 18%; risk ratio 2.3, 95% CI 1.3-4.2; p = 0.003). Conclusion The DDR-IF score unifies measures of genomic instability and immune contexture to identify a therapeutically vulnerable subset of ES-SCLC patients most likely to benefit from PARP-ICB synergy. It represents a promising, though exploratory, framework for personalizing immunotherapy in ES-SCLC, whose clinical utility requires confirmation in prospective multicenter trials.

Source: Frontiers in Oncology

DOI: 10.3389/fonc.2025.1680921

Authors: Yinxu Zhang, Xiaoyang Chen, Dai Wang, Xuan Zhou, Yuxi Wang, Guangyu Zhang, Xiaomei Liu

Institutions: Jinzhou Medical University, Medical College of Jinzhou Medical University

Language: English

Topic: Lung Cancer Research Studies

Subfield: Oncology

Field: Medicine

Domain: Health Sciences

SDG: Good health and well-being

Open Access status: gold

Estimated APC paid: $3,801