PAPPA2 mutation as a novel indicator stratifying beneficiaries of immune checkpoint inhibitors in skin cutaneous melanoma and non‐small cell lung cancer. Issue 9 (10th July 2022)

• Record Type: Journal Article
• Authors: Dong, Yiting; Zhao, Lele; Duan, Jianchun; Bai, Hua; Chen, Dongsheng; Li, Si; Yu, Yangyang; Xiao, Mingzhe; Zhang, Qin; Duan, Qianqian; Sun, Tingting; Qi, Chuang; Wang, Jie; Wang, Zhijie
• Is Part Of: Cell proliferation. Volume 55:Issue 9(2022)
• Page Start: n/a
• Page End: n/a
• Publication Date: 2022-07-10
• Subjects: Cell proliferation -- Periodicals; 571.84
• DOI: 10.1111/cpr.13283
• Languages: English
• ISSNs: 0960-7722

Abstract

Abstract: Background: Pappalysin 2 ( PAPPA2 ) mutation, occurring most frequently in skin cutaneous melanoma (SKCM) and non‐small cell lung cancer (NSCLC), is found to be related to anti‐tumour immune response. However, the association between PAPPA2 and the efficacy of immune checkpoint inhibitors (ICIs) therapy remains unknown. Methods: To analyse the performance of PAPPA2 mutation as an indicator stratifying beneficiaries of ICIs, seven public cohorts with whole‐exome sequencing (WES) data were divided into the NSCLC set ( n = 165) and the SKCM set ( n = 210). For further validation, 41 NSCLC patients receiving anti‐PD‐(L)1 treatment were enrolled in China cohort ( n = 41). The mechanism was explored based on The Cancer Genome Atlas database ( n = 1467). Results: In the NSCLC set, patients with PAPPA2 mutation (PAPPA2‐Mut) demonstrated a significantly superior progress free survival (PFS, hazard ratio [HR], 0.28 [95% CI, 0.14–0.53]; p < 0.001) and objective response rate (ORR, 77.8% vs. 23.2%; p < 0.001) compared to those with wide‐type PAPPA2 (PAPPA2‐WT), consistent in the SKCM set (overall survival, HR, 0.49 [95% CI: 0.31–0.78], p < 0.001; ORR, 34.1% vs. 16.9%, p = 0.039) and China cohort. Similar results were observed in multivariable models. Accordingly, PAPPA2 mutation exhibited superior performance in predicting ICIs efficacy compared with other published ICIs‐related gene mutations, such as EPHA family, MUC16, LRP1B and TTN, etc. In addition, combined utilization of PAPPA2 mutation and tumour mutational burden (TMB) could expand the identification of potential responders to ICIs therapy in both NSCLC set (HR, 0.36 [95% CI: 0.23–0.57], p < 0.001) and SKCM set (HR, 0.51 [95% CI: 0.34–0.76], p < 0.001). Moreover, PAPPA2 mutation was correlated with enhanced anti‐tumour immunity including higher activated CD4 memory T cells level, lower Treg cells level, and upregulated DNA damage repair pathways. Conclusions: Our findings indicated that PAPPA2 mutation could serve as a novel indicator to stratify beneficiaries from ICIs therapy in NSCLC and SKCM, warranting further prospective studies. Abstract : Flow diagram of the study. (A) Preliminary analysis. PAPPA2 mutated most frequently in skin cutaneous melanoma (SKCM) and non‐small cell lung cancer (NSCLC) in the The Cancer Genome Atlas (TCGA) database. PAPPA2 mutational rates in patients with objective response (CR + PR) versus without (SD + PD) were compared with other immune checkpoint inhibitors‐related gene mutations in the NSCLC and SKCM sets. (B) Biomarker development. Association between PAPPA2 mutation and clinical outcomes has been analysed in the NSCLC set, the SKCM set and China cohort. (C) Mechanism exploring. Based on the TCGA database, the correlation of PAPPA2 mutation with tumour mutation burden, infiltrating immune cells and DNA damage repair was explored for further immunogenicity and anti‐tumour activity mechanisms.