Mutations of PI3K-AKT-mTOR pathway as predictors for immune cell infiltration and immunotherapy efficacy in dMMR/MSI-H gastric adenocarcinoma
Zhenghang Wang, Xinyu Wang, Yu Xu, Jian Li, Xiaotian Zhang, Zhi Peng, Yajie Hu, Xinya Zhao, Kun Dong, Bei Zhang, Chan Gao, Xiaochen Zhao, Hui Chen, Jinping Cai, Yuezong Bai, Yu Sun, Lin Shen
Abstract
Abstract 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.