Cargando…

Mutations of PI3K-AKT-mTOR pathway as predictors for immune cell infiltration and immunotherapy efficacy in dMMR/MSI-H gastric adenocarcinoma

BACKGROUND: A significant subset of mismatch repair-deficient (dMMR)/microsatellite instability-high (MSI-H) gastric adenocarcinomas (GAC) are resistant to immune checkpoint inhibitors (ICIs), yet the underlying mechanism remains largely unknown. We sought to investigate the genomic correlates of th...

Descripción completa

Detalles Bibliográficos
Autores principales: Wang, Zhenghang, Wang, Xinyu, Xu, Yu, Li, Jian, Zhang, Xiaotian, Peng, Zhi, Hu, Yajie, Zhao, Xinya, Dong, Kun, Zhang, Bei, Gao, Chan, Zhao, Xiaochen, Chen, Hui, Cai, Jinping, Bai, Yuezong, Sun, Yu, Shen, Lin
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9022268/
https://www.ncbi.nlm.nih.gov/pubmed/35443723
http://dx.doi.org/10.1186/s12916-022-02327-y
Descripción
Sumario:BACKGROUND: A significant subset of mismatch repair-deficient (dMMR)/microsatellite instability-high (MSI-H) gastric adenocarcinomas (GAC) are resistant to immune checkpoint inhibitors (ICIs), yet the underlying mechanism remains largely unknown. We sought to investigate the genomic correlates of the density of tumor-infiltrating immune cells (DTICs) and primary resistance to ICI treatment. METHODS: Four independent cohorts of MSI-H GAC were included: (i) the surgery cohort (n = 175) with genomic and DTIC data, (ii) the 3DMed cohort (n = 32) with genomic and PD-L1 data, (iii) the Cancer Genome Atlas (TCGA) cohort (n = 73) with genomic, transcriptomic, and survival data, and (iv) the ICI treatment cohort (n = 36) with pre-treatment genomic profile and ICI efficacy data. RESULTS: In the dMMR/MSI-H GAC, the number of mutated genes in the PI3K-AKT-mTOR pathway (NMP) was positively correlated with tumor mutational burden (P < 0.001) and sensitivity to PI3K-AKT-mTOR inhibitors and negatively correlated with CD3(+) (P < 0.001), CD4(+) (P = 0.065), CD8(+) (P = 0.004), and FOXP3(+) cells (P = 0.033) in the central-tumor rather than invasive-margin area, and the transcription of immune-related genes. Compared to the NMP-low (NMP = 0/1) patients, the NMP-high (NMP ≥ 2) patients exhibited a poorer objective response rate (29.4% vs. 85.7%, P < 0.001), progression-free survival (HR = 3.40, P = 0.019), and overall survival (HR = 3.59, P = 0.048) upon ICI treatment. CONCLUSIONS: Higher NMP was identified as a potential predictor of lower DTICs and primary resistance to ICIs in the dMMR/MSI-H GAC. Our results highlight the possibility of using mutational data to estimate DTICs and administering the PI3K-AKT-mTOR inhibitor as an immunotherapeutic adjuvant in NMP-high subpopulation to overcome the resistance to ICIs. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12916-022-02327-y.