A Self-Attention-Based Neural Network for Predicting Immune Checkpoint Inhibitors Response.

Abstract

Cancer cells evade immune system by negatively regulating T cells via immune checkpoints (e.g., PD-1). By blocking these checkpoints, the ability of immune system to recognize and kill cancer cells restores. Individual response rate of checkpoint blockade varies among patients, with 50%-80% in specific types of cancer such as melanoma, while only 15%-30% in most other tumors. Yet it is still an open question what is the set of biomarkers that are crucial to the response to immune checkpoint inhibitors (ICI). The overall goal of this study is to develop and validate a biologically-aware interpretable deep learning model to identify the biomarkers that can predict the survival outcome to ICI treatment. The self-attention mechanism could yield interpretable results where important biomarkers may have more "attention". However, in classical self-attention mechanism, the prior biological knowledge of protein interactions (PPI) and gene pathways are not incorporated. In this study, we propose a weighted biologically-aware attention score, where it is weighted against the gene centrality and pathway length. The genes that are closely connected to mutated genes receive 'high attention', while the genes that are far away from mutated genes along the pathway receive "lower attention". We then train, validate and test our model using 1,660 patients of nine types of cancer. To validate the prediction, 1. We evaluate the accuracy via concordance index. 2. We identified the genes that receive high attention and verify their functions in existed literature. 3. We perform sanity check by removing these genes from the data, re-training and predicting again, and comparing the prediction accuracy. Our framework has achieved an average accuracy (measured via c-index) of 0.60 ± 0.06 for NSCLC and 0.58 ± 0.07 for melanoma, which is superior to both the gold standard COX-PH model (0.57 ± 0.06 for NSCLC and 0.53 ± 0.03 for melanoma) and DeepSurv (0.54 ± 0.05 for NSCLC and 0.51 ± 0.10 for melanoma). Genes that receive high attention have been validated by supporting literature, which provides an additional means of verifying the prediction in comparison to "black box" deep learning models, where there is no way to comprehend the reason behind predictions. Removing the top 8% high-attention genes (∼25 genes) from the data while using the remaining 92% for making predictions resulted in a drop in accuracy to 0.55 ± 0.073 for NSCLC and 0.56 ± 0.03 for melanoma, underscoring the significance of these genes. Patient stratification is also performed by dividing patients into responders and non-responders based on prediction score. In this study, we propose and validate a biologically-aware self-attention based deep learning model which outperforms commonly-used survival models. Additionally, this tool has the potential to identify key biomarkers while assist in clinical decision-making, which demonstrates a promising step for immunotherapy response prediction.