The microbiome and response to immunotherapy: the aging population and considerations for microbial modifications
Background
Lung cancer is a disease that disproportionately affects the elderly. The prognosis for lung cancer has improved in recent years in large part due to a class of drugs called immune checkpoint inhibitors (ICIs). However, older adults are poorly represented in clinical trials and many do not respond to treatment. The microbiome has been shown to affect response to ICIs (defined as complete response, partial response or stable disease by RECIST v1.1); several independent studies reported taxa enriched in individuals who responded to treatment. Moreover, in pre-clinical models non-responder mice could be made to respond by supplementation with a microbe that was enriched in the responder group. However, the gut microbiome changes with age. It has not been studied how the age affected microbes relate to those that promote response to ICIs.
Methods
A review of the literature was performed to find associations between microbe taxa and either age or immunotherapy outcomes. This information was compiled for analysis.
Results
There were five references reporting differences in the microbiomes of individuals who respond to ICIs vs those who did not. Within, 423 taxa were found to be enriched in responders vs non, with 42% agreement between the references. There were 33 reports of age-related changes in the microbiome. From these, 20 taxa were found to be enriched in older adults and 13 depleted. Overlapping taxa between the responders and older adults showed that roughly half of the taxa enriched in responders were found in older adults, and half in younger.
Conclusions
These results suggest that age-related changes to the microbiome may affect response to ICIs. Age and baseline microbiome state should be considered when designing methods to rationally manipulate microbial communities to promote response to ICIs.
Interesting project, with potential implications for many different types of cancer. I did not realize that age-related changes in the microbiome were so pronounced. Can you speculate about how microbiome composition could modulate the response to immune checkpoint inhibitors?
Absolutely, though there is not much agreement on what microbes are the largest predictors on response or non-response. It seems that some microbes or combination of microbes promote a stronger immune response.
Gopalakrishnan, V., et al. “Gut microbiome modulates response to anti–PD-1 immunotherapy in melanoma patients.” Science 359.6371 (2018): 97-103.