Abstract
Simple SummaryThe immune checkpoint blockade (ICB), and concretely the blockade of the PD1/PDL1 axis, has opened up a new standard of treatment for non-small cell lung cancer (NSCLC). However, despite substantial advances in clinical care, many patients still remain refractory to these therapies. Biomarkers such as PD-L1 expression and tumor mutational burden have been associated with ICB efficacy, but the mechanisms underlying variable responses are not yet fully understood. Recently, the differential composition of the gut microbiota was studied as one of the variables accounting for interpatient heterogeneity in ICB responses. To better understand the potential role of the gut microbiota as a biomarker for immunotherapy, we prospectively collected microbiota samples from advanced NSCLC patients starting treatment with ICB. The identification of certain bacteria genera associated with clinical outcomes to ICB in NSCLC may provide novel potential predictive and prognostic biomarkers useful for patient selection and therapy optimization.Background: The human gut harbors around 1013–1014 microorganisms, collectively referred to as gut microbiota. Recent studies have found that the gut microbiota may have an impact on the interaction between immune regulation and anti-cancer immunotherapies. Methods: In order to characterize the diversity and composition of commensal microbiota and its relationship with response to immune checkpoint blockade (ICB), 16S ribosomal DNA (rDNA) sequencing was performed on 69 stool samples from advanced non-small cell lung cancer (NSCLC) patients prior to treatment with ICB. Results: The use of antibiotics and ICB-related skin toxicity were significantly associated with reduced gut microbiota diversity. However, antibiotics (ATB) usage was not related to low ICB efficacy. Phascolarctobacterium was enriched in patients with clinical benefit and correlated with prolonged progression-free survival, whereas Dialister was more represented in patients with progressive disease, and its higher relative abundance was associated with reduced progression-free survival and overall survival, with independent prognostic value in multivariate analysis. Conclusions: Our results corroborate the relation between the baseline gut microbiota composition and ICB clinical outcomes in advanced NSCLC patients, and provide novel potential predictive and prognostic biomarkers for immunotherapy in NSCLC.
Highlights
Lung cancer is one of the most lethal cancers worldwide [1,2]
Correlation analysis revealed that gender, body mass index, and progression disease (PD)-L1 expression were clinical factors associated with response to immune checkpoint blockade (ICB) in this cohort (Table 1)
Univariate Cox regression analysis evidenced that Progression-free survival (PFS) was significantly shorter in women, patients with poor Eastern cooperative oncology group (ECOG) performance status, and patients with low PD-L1 expression, whereas prolonged overall survival (OS) was observed in patients with high body mass index (Table S2)
Summary
Lung cancer is one of the most lethal cancers worldwide [1,2]. Non-small cell lung cancer (NSCLC) constitutes approximately 85% of all lung cancers and includes adenocarcinoma, squamous cell carcinoma (SCC), and large cell carcinoma as the main histological subtypes [3,4]. The treatment of NSCLC has changed in recent years with the initial success of immunotherapy, especially that based on immune checkpoint blockade (ICB) with monoclonal antibodies against cytotoxic T lymphocyte-associated protein 4 (CTLA-4) or programmed cell death protein 1 (PD-1) and its ligand (PD-L1). The PD-1/PD-L1 axis has been demonstrated to influence the balance between tumor immune surveillance and immune resistance In this sense, elevated PD-L1 expression on tumor cells results in. Methods: In order to characterize the diversity and composition of commensal microbiota and its relationship with response to immune checkpoint blockade (ICB), 16S ribosomal DNA (rDNA) sequencing was performed on 69 stool samples from advanced non-small cell lung cancer (NSCLC) patients prior to treatment with ICB. Results: The use of antibiotics and ICB-related skin toxicity were significantly associated with reduced gut microbiota diversity. Phascolarctobacterium was enriched in patients with clinical benefit and correlated with prolonged progression-free survival, whereas Dialister was more represented in patients with progressive disease, and its higher relative abundance was associated with reduced progressionfree survival and overall survival, with independent prognostic value in multivariate analysis
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