The lung microbiome, peripheral gene expression, and recurrence-free survival after resection of stage II non-small cell lung cancer

Abstract

Background Cancer recurrence after tumor resection in early-stage non-small cell lung cancer (NSCLC) is common, yet difficult to predict. The lung microbiota and systemic immunity may be important modulators of risk for lung cancer recurrence, yet biomarkers from the lung microbiome and peripheral immune environment are understudied. Such markers may hold promise for prediction as well as improved etiologic understanding of lung cancer recurrence. Methods In tumor and distant normal lung samples from 46 stage II NSCLC patients with curative resection (39 tumor samples, 41 normal lung samples), we conducted 16S rRNA gene sequencing. We also measured peripheral blood immune gene expression with nanoString®. We examined associations of lung microbiota and peripheral gene expression with recurrence-free survival (RFS) and disease-free survival (DFS) using 500 × 10-fold cross-validated elastic-net penalized Cox regression, and examined predictive accuracy using time-dependent receiver operating characteristic (ROC) curves. Results Over a median of 4.8 years of follow-up (range 0.2–12.2 years), 43% of patients experienced a recurrence, and 50% died. In normal lung tissue, a higher abundance of classes Bacteroidia and Clostridia, and orders Bacteroidales and Clostridiales, were associated with worse RFS, while a higher abundance of classes Alphaproteobacteria and Betaproteobacteria, and orders Burkholderiales and Neisseriales, were associated with better RFS. In tumor tissue, a higher abundance of orders Actinomycetales and Pseudomonadales were associated with worse DFS. Among these taxa, normal lung Clostridiales and Bacteroidales were also related to worse survival in a previous small pilot study and an additional independent validation cohort. In peripheral blood, higher expression of genes TAP1, TAPBP, CSF2RB, and IFITM2 were associated with better DFS. Analysis of ROC curves revealed that lung microbiome and peripheral gene expression biomarkers provided significant additional recurrence risk discrimination over standard demographic and clinical covariates, with microbiome biomarkers contributing more to short-term (1-year) prediction and gene biomarkers contributing to longer-term (2–5-year) prediction. Conclusions We identified compelling biomarkers in under-explored data types, the lung microbiome, and peripheral blood gene expression, which may improve risk prediction of recurrence in early-stage NSCLC patients. These findings will require validation in a larger cohort.

The Diversity of the Microbiome Impacts Chronic Lymphocytic Leukemia Development in Mice and Humans

“…In our study, the presence of these bacteria in the LH mice could however have bene cial effects, perhaps by shaping myeloid cells into a phenotype that is less supportive of CLL growth. Lastly, Bacteroidales, also upregulated in this group and considered to be bene cial for gut health, but also correlated with worse disease outcome in lung cancer patients (45,46), could be priming the gut-associated immune system in the LH mice and contributing to its immune-protective action against leukemia development.…”

High-Throughput Antigen Microarray Identifies Longitudinal Prognostic Autoantibody for Chemoimmunotherapy in Advanced Non-Small Cell Lung Cancer

“…The absence of tapasin hampers the antigen processing of tumor-associated antigens and leads to evasion of tumor-associated antigen–specific CTLs recognition, leading to poorer prognosis (such as colorectal cancer, glioblastoma, and NSCLC), tumor progression and metastasis, and lower CD8 + T tumor-infiltrating lymphocytes ( 42 , 43 , 44 , 45 , 46 ). In NSCLC, elevated TAPBP gene expression in peripheral blood has been associated with improved disease-free survival, and tapasin expression in tumor samples has been positively correlated with better OS ( 44 , 47 ). In melanoma patients, high tapasin expression has been associated with favorable responses to immunotherapy ( 48 ).…”

Peripheral blood CD3+HLADR+ cells and associated gut microbiome species predict response and overall survival to immune checkpoint blockade

“…As already dissected by many reviews, the gut microbiome, despite its irrefutable role in immune modulation and its in uence in cancer immunotherapy, is highly prone to uctuation with many different studies reporting different prognostically relevant taxa, due to factors such as geography and different enterotypes, lifestyle and diet, different techniques to analyze samples and reference databases [43,44]. The relative abundance of the Burkholderiales order has been shown to impact relapse free survival (RFS) in lung tissue after resection of stage II cancer [45]. In the gut, some genus inside this order have been shown in the past as successful predictors of OS, such as Burkhorderiales spp., whose supplementation lead to recovery of response to anti-CTLA4 treatment in melanoma mice by inducing interleukin 12 (IL-12)-dependent TH 1…”