Prospective correlation between the patient microbiome with response to and development of immune-mediated adverse effects to immunotherapy in lung cancer

Abstract

Background Though the gut microbiome has been associated with efficacy of immunotherapy (ICI) in certain cancers, similar findings have not been identified for microbiomes from other body sites and their correlation to treatment response and immune related adverse events (irAEs) in lung cancer (LC) patients receiving ICIs. Methods We designed a prospective cohort study conducted from 2018 to 2020 at a single-center academic institution to assess for correlations between the microbiome in various body sites with treatment response and development of irAEs in LC patients treated with ICIs. Patients must have had measurable disease, ECOG 0–2, and good organ function to be included. Data was collected for analysis from January 2019 to October 2020. Patients with histopathologically confirmed, advanced/metastatic LC planned to undergo immunotherapy-based treatment were enrolled between September 2018 and June 2019. Nasal, buccal and gut microbiome samples were obtained prior to initiation of immunotherapy +/− chemotherapy, at development of adverse events (irAEs), and at improvement of irAEs to grade 1 or less. Results Thirty-seven patients were enrolled, and 34 patients were evaluable for this report. 32 healthy controls (HC) from the same geographic region were included to compare baseline gut microbiota. Compared to HC, LC gut microbiota exhibited significantly lower α-diversity. The gut microbiome of patients who did not suffer irAEs were found to have relative enrichment of Bifidobacterium (p = 0.001) and Desulfovibrio (p = 0.0002). Responders to combined chemoimmunotherapy exhibited increased Clostridiales (p = 0.018) but reduced Rikenellaceae (p = 0.016). In responders to chemoimmunotherapy we also observed enrichment of Finegoldia in nasal microbiome, and increased Megasphaera but reduced Actinobacillus in buccal samples. Longitudinal samples exhibited a trend of α-diversity and certain microbial changes during the development and resolution of irAEs. Conclusions This pilot study identifies significant differences in the gut microbiome between HC and LC patients, and their correlation to treatment response and irAEs in LC. In addition, it suggests potential predictive utility in nasal and buccal microbiomes, warranting further validation with a larger cohort and mechanistic dissection using preclinical models. Trial registration ClinicalTrials.gov, NCT03688347. Retrospectively registered 09/28/2018.

Tying Small Changes to Large Outcomes: The Cautious Promise in Incorporating the Microbiome into Immunotherapy

“…Our systematic review noted these same trends across various solid tumor types receiving ICIs [ 58 ]. In addition to mirroring these findings, our research also found that increased Proteobacteria are similarly associated with decreased likelihood of irAE development [ 20 ].…”

“…Other studies have linked ICI outcomes in nonmelanomatous cancers to gut microbiome composition. We found a similar association between Firmicutes and ICI response in our 16S evaluation of lung cancer patients [ 20 ]; these findings were echoed in a separate cohort that had undergone whole genome shotgun sequencing [ 48 ]. Routy et al found that Akkermansia , a member of the phylum Verrucomicrobia , was enriched in NSCLC patients who responded to ICI.…”

“…In our and others’ research, lung cancer patients had different gut and respiratory microbiome compositions compared to their healthy controls [ 18 , 19 , 20 ]. Zhuang et al found reduced enrichment of Actinobacteria in the gut microbiome of lung cancer patients [ 18 ].…”

“…To date, several studies regarding the gut microbiome and immunotherapy efficacy have been performed [ 15 , 20 , 47 , 48 , 49 , 50 , 51 , 52 ]. The majority of initial studies focused on patients treated for melanoma, a disease with high propensity for response to immunotherapy; this has since broadened to include multiple tumor types.…”

“…As previously seen, much attention has been paid to changes in the gut microbiome, but given the finding by Jin et al with respect to local bacterial factors in pulmonary carcinogenesis [ 32 ], it seems prudent to explore the contribution of the respiratory microbiome to ICI efficacy in lung cancer, and a possible correlation between lung and gut microbiomes. We are probably the first to address this question by analyzing the nasal and buccal microbiome given its proximity to the lungs: we observed that enrichment of Finegoldia (of phylum Firmicutes ) in nasal and Megasphaera (also of phylum Firmicutes ) in buccal swabs correlated with better response in NSCLC patients treated with chemoimmunotherapy [ 20 ].…”