In:
Cell Proliferation, Wiley, Vol. 55, No. 9 ( 2022-09)
Abstract:
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.
Type of Medium:
Online Resource
ISSN:
0960-7722
,
1365-2184
Language:
English
Publisher:
Wiley
Publication Date:
2022
detail.hit.zdb_id:
2019986-7
SSG:
12
