Exploring Gut Microbiome in Predicting the Efficacy of Immunotherapy in Non-Small Cell Lung Cancer

SIMPLE SUMMARY: Despite the emerging success of immunotherapy in non-small-cell lung cancer (NSCLC), it remains clinically important to better identify patients who are likely to respond to treatment, especially considering the existence of immune-related adverse events (irAEs). In recent years, the gut microbiome has been correlated with treatment response, but no predictive models relating the two have been developed. In this study, we used random forest and neural networks to predict the progression-free survival of NSCLC patients treated with immunotherapy. Our results showed that a functional profile of the human gut microbiome outperformed the taxonomical profile across different studies, which can be utilized to establish a model with good predictive value in lung cancer immunotherapy. ABSTRACT: We performed various analyses on the taxonomic and functional features of the gut microbiome from NSCLC patients treated with immunotherapy to establish a model that may predict whether a patient will benefit from immunotherapy. We collected 65 published whole metagenome shotgun sequencing samples along with 14 samples from our previous study. We systematically studied the taxonomical characteristics of the dataset and used both the random forest (RF) and the multilayer perceptron (MLP) neural network models to predict patients with progression-free survival (PFS) above 6 months versus those below 3 months. Our results showed that the RF classifier achieved the highest F-score (85.2%) and the area under the receiver operating characteristic curve (AUC) (95%) using the protein families (Pfam) profile, and the MLP neural network classifier achieved a 99.9% F-score and 100% AUC using the same Pfam profile. When applying the model trained in the Pfam profile directly to predict the treatment response, we found that both trained RF and MLP classifiers significantly outperformed the stochastic predictor in F-score. Our results suggested that such a predictive model based on functional (e.g., Pfam) rather than taxonomic profile might be clinically useful to predict whether an NSCLC patient will benefit from immunotherapy, as both the F-score and AUC of functional profile outperform that of taxonomic profile. In addition, our model suggested that interactive biological processes such as methanogenesis, one-carbon, and amino acid metabolism might be important in regulating the immunotherapy response that warrants further investigation.