The influence of the gut microbiome on immune checkpoint blockade therapy of cancer

Immune checkpoint blockade (ICB) therapy has achieved great success as an advanced tumor therapy during the last ten years. Especially the many metastatic cancer patients that have acquired resistance against traditional cancer therapies show prolonged clinical benefit. One of the significant challenges is that the response rate of ICB therapy is still low. In previous studies, the gut microbiota has been reported as one of the promising factors associated with the efficacy of ICB immunotherapy. However, since the studies of the influence of the gut microbiota on efficacy of immunotherapies started in 2015, our knowledge into this is still in its primary stages, and several issues remain to be solved. Firstly, due to the diversity of the human gut microbiota across populations, different studies within different cohorts report different conclusions, which suggest that more comprehensive data need to be collected to obtain solid conclusion. Secondly, the existing studies about the influence of the gut microbiota on the response to immunotherapy have only covered limited cancer types. Several other cancers, including nasopharyngeal carcinoma (NPC), have yet to be investigated. Thirdly, ICB based combination therapies that appeared recently have shown improved therapeutic efficacy, but the role of gut microbiota on the clinical outcome remains to be studied. This PhD thesis mainly address parts of these three issues.

In the first study, a cohort of 85 non-small cell lung cancer (NSCLC) patients that received immune checkpoint inhibitors (ICIs) was enrolled and fecal samples were collected longitudinally and subjected for shotgun metagenomics analysis. We identified enrichment of the gut bacterium Akkermansia muciniphila in responders to the ICI therapy. Additional factors such as tumor mutation burden (TMB) and human leukocyte antigen (HLA) heterozygosity were also identified to affect progression-free survival of the patients. Based on the collected omics data, a prediction model was successfully constructed that emphasized the potential for gut bacterial species to predict the response outcome in patients receiving immunotherapy.

In the second study, we studied response factors in a cohort of 52 NPC patients undergoing ICI therapy. Unlike NSCLC, we observed that gut microbial diversity did not differ between ICI responders and non-responders. We identified that seven gut bacteria, including Blautia wexlera and Blautia obeum, were enriched at baseline in non-responders, and also found other factors, including TMB, HLA-I heterozygosity and blood Epstein-Barr virus (EBV) load, to affect the clinical outcome in NPC patients significantly.

In the third study, the association between the gut microbiota and ICI-based combinational therapies was investigated based on data from 50 patients with advanced melanoma. Results showed combined ICIs with chemotherapy or targeted therapy resulted in a reduced gut bacterial diversity in patients as compared to ICI monotherapy. We also found that the influence of specific bacteria such as Faecalibacterium prausnitzii might affect the response to ICB immunotherapy.

Combined these data may help improve our understanding of the interlinkage between the gut microbiota and the ICI treatment response, and eventually help foster development of new probiotics to improve the response rate to ICI in cancer patients.