NEW YORK – New research suggests that gut microbial communities found in aging individuals with cancer and features of their tumor microenvironment can boost their response to checkpoint blockade immunotherapy. Moreover, treatment with an age-related gut microbial enterotype may enhance the effectiveness of such treatments.
"These findings hold significant promise for clinical applications, offering prospects for tailored immunotherapeutic strategies," co-corresponding author Haoyan Chen of Shanghai Jiao Tong University and his colleagues wrote in Cell Host and Microbe on Wednesday, adding that the "ability to identify patients who are likely to respond favorably to immunotherapy based on their gut microbiota profile opens the door to personalized treatment approaches."
The team began with a retrospective meta-analysis focused on immunotherapy response in relation to patient age, using data for 2,985 individuals with clear cell renal cell carcinoma, non-small cell lung cancer (NSCLC), melanoma, gastric cancer, or brain cancer who participated in 25 immune checkpoint blockade (ICB) immunotherapy trials.
When they compared both treatment response and durable clinical benefits of participants, they found an uptick in checkpoint blockade therapy response in increasingly older individuals, even after taking participants' biological sex, drug usage, and cancer type into account. Digging into this trend further, they found that treatment response was broadly distinct in patients who were older or younger than about 60 years.
In an effort to understand this age-related response pattern, the team turned to single-cell RNA sequencing profiles from 52 NSCLC patients, 62 individuals with colorectal cancer, 26 gastric cancer patients, and 10 individuals with hepatocellular carcinoma, pinpointing ICB treatment response-associated T-cell markers that reflected immune features in the tumor microenvironment.
Such findings were most marked when comparing patients at opposite ends of the age spectrum, but more muted across the middle-aged groups, they noted.
"Intriguingly, T cells from older patients showed higher exhausted and cytotoxic scores, which were further validated in another NSCLC, colorectal cancer, gastric cancer, and hepatocellular carcinoma cohort as well as at the pan-cancer level," the authors reported, arguing that the results "imply that changes in T-cell function may contribute to the heightened responsiveness to ICB therapy observed in extreme older patients."
From there, the researchers searched for gut microbial community features that tracked with the ICB treatment response and tumor microenvironment patterns uncovered in the initial analyses, reasoning that past studies had uncovered gut microbe-linked immunotherapy modulating effects.
Using metagenomic sequencing on fecal samples from 782 patients being treated with ICB immunotherapy, the team narrowed in on gut microbe enterotypes that appeared to coincide with advanced age and response to the treatment. On the other hand, the proportion of patients responding to treatment appeared to dip in a subset of 114 patients over 60 who were also being treated with antibiotics.
The researchers also analyzed clinical and metagenomic data from more than 800 additional ICB-treated individuals, including 25 initially treatment-refractory melanoma patients who responded after receiving fecal microbiota transplants (FMT) from melanoma patients who did respond to ICB treatment.
The team's follow-up mouse model experiments, meanwhile, found that both younger and older mice with colon adenocarcinoma tended to respond to anti-PD-1 treatment, though the extent of tumor growth reduction appeared to be more pronounced in mice over 14 months old.
The researchers also showed that mouse models exhibited tumor microenvironment changes — including enhanced T-cell activation — and response to anti-PD-1 checkpoint blockade treatment after receiving FMT from humans with the so-called "aging-enriched" gut microbial enterotype.
Together, the authors suggested, the results "highlight the importance of considering age-related immune changes and gut microbiota composition in tailoring immunotherapy strategies for patients with cancers."