A genomic mutation signature predicts the clinical outcomes of immunotherapy and characterizes immunophenotypes in gastrointestinal cancer

Xi Jiao,Yujiao Wang,Zhi Peng,Zhenghang Wang,Jian Li,Xin Wei,Lin Shen,Zhihao Lu,Chang Liu,Xicheng Wang,Na Zhuo,Huan Chen,Shuang Li,Xiaotian Zhang,Henghui Zhang,Yanni Wang,Changsong Qi,Jifang Gong

doi:10.1038/s41698-021-00172-5

Abstract

The association between genetic variations and immunotherapy benefit has been widely recognized, while such evidence in gastrointestinal cancer remains limited. We analyzed the genomic profile of 227 immunotherapeutic gastrointestinal cancer patients treated with immunotherapy, from the Memorial Sloan Kettering (MSK) Cancer Center cohort. A gastrointestinal immune prognostic signature (GIPS) was constructed using LASSO Cox regression. Based on this signature, patients were classified into two subgroups with distinctive prognoses (p < 0.001). The prognostic value of the GIPS was consistently validated in the Janjigian and Pender cohort (N = 54) and Peking University Cancer Hospital cohort (N = 92). Multivariate analysis revealed that the GIPS was an independent prognostic biomarker. Notably, the GIPS-high tumor was indicative of a T-cell-inflamed phenotype and immune activation. The findings demonstrated that GIPS was a powerful predictor of immunotherapeutic survival in gastrointestinal cancer and may serve as a potential biomarker guiding immunotherapy treatment decisions.

Highlights

Immune checkpoint inhibitors (ICIs) have revolutionized the therapeutic landscape of various cancers, including gastrointestinal cancer
Clinicopathological features of the patients In this study, we developed a prediction model based on the Memorial Sloan Kettering (MSK) cohort of 227 gastrointestinal cancer patients who had received ICIs (MSK-GI cohort; esophagogastric cancer, N = 118; colorectal cancer, N = 109)[13] and with a median follow-up of 19 months
In this study, we developed and validated a genomic classifier, gastrointestinal immune prognostic signature (GIPS), consisting of six genes that can better predict the efficacy of ICI therapy in gastrointestinal cancer patients

Summary

Introduction

Immune checkpoint inhibitors (ICIs) have revolutionized the therapeutic landscape of various cancers, including gastrointestinal cancer. Only high microsatellite instability (MSI-H) has been validated in clinical scenarios and programmed death ligand-1 (PD-L1) expression is an important but imperfect predictive biomarker in gastrointestinal cancer with controversial results across different trials[3,4,5,6,7,8,9] Transcriptomic biomarkers such as the T-cell-inflamed gene expression profile (GEP) were shown to be associated with the response to ICIs, but failed to predict survival in gastric or esophageal cancer[10,11]. Emerging data indicate that not all genetic mutations are equivalent in terms of their immunologic impact Some mutations, such as ARID1A, TP53, PBRM1, KEAP1, STK11, NOTCH1/2/3, and JAK1/2, may exert positive or negative influences on the outcomes of ICI treatment[14,15,16,17,18,19]. All of these mutations are weighted the same in TMB scoring systems, highlighting the limitations of TMB as a predictive biomarker for ICI

Methods

Results

Conclusion