Abstract
Simple SummaryWhile modulating gut microbiota using dietary intervention with natural nutrients has proven to be effective in improving the response rate of immune checkpoint inhibitors (ICIs), the underpinning mechanism is poorly understood. This work demonstrates that the oral administration of ultrafine jujube powder (JP) let to a significant alteration of gut microbiota, an increased abundance of Clostridiales, including Ruminococcaceae and Lachnospiraceae, an elevated SCFA production, an intensified infiltration of CD8+ T cells to the tumor microenvironment, and a greatly improved response of anti-PD-L1 treatment against murine colon adenocarcinoma. Moreover, the size of the JP particles had a significant impact on the abovementioned attributes. The present study demonstrates that dietary intervention with nutrients is highly effective in modulating the gut microbiota for an improved immune checkpoint blockage therapy.Whereas dietary intervention with natural nutrients plays an important role in activating the immune response and holds unprecedented application potential, the underpinning mechanism is poorly understood. The present work was dedicated to comprehensively examine the effects of ultrafine jujube powder (JP) on the gut microbiota and, consequentially, the effects associated with the response rate to anti-PD-L1 treatment against murine colon adenocarcinoma. A murine colon adenocarcinoma model with anti-PD-L1 immunotherapy was established to evaluate how dietary interventions affect the microbiota. In vitro and in vivo experiments confirmed the role of SCFAs in the immune response. Oral administration of JP greatly improves the response of anti-PD-L1 treatment against murine colon adenocarcinoma. Such an improvement is associated with the alteration of gut microbiota which leads to an increased abundance of Clostridiales, including Ruminococcaceae and Lachnospiraceae, an elevated SCFA production, and an intensified infiltration of CD8+ T cells to the tumor microenvironment. This work demonstrates that JP is particularly effective in modulating the gut microbiota for an improved immune checkpoint blockage therapy by boosting cytotoxic CD8+ T cells in tumor-infiltrating lymphocytes. The experimental findings of the present study are helpful for the development of dietary intervention methods for cancer immunotherapy using natural nutrients.
Highlights
While immune checkpoint inhibitors (ICIs) targeting programmed cell death ligand1 (PD-1) or cytotoxic T lymphocyte-associated protein-4 (CTLA-4) have achieved tumor regression in several cancers [1,2], the unexpected low response rate, typically below30%, hinders the full display of this revolutionary procedure [3]
We demonstrated that the oral admission of jujube enriched the abundance of Lachnospiraceae while it reduced that of Prevotellaceae, thereby improving the therapeutic efficiency and response rate of anti-PD-L1 against murine colon adenocarcinoma [26]
We discovered that oral administration of jujube powder (JP) is able to ameliorate the mouse gut biota with an enriched population of Lachnospiraceae and Ruminococcaceae, an enhanced production of short-chain fatty acid (SCFA), and an improved tumor immune infiltration and systemic immunity, which collectively contribute to the higher antitumor efficiency of αPD-L1 in vivo
Summary
While immune checkpoint inhibitors (ICIs) targeting programmed cell death ligand1 (PD-1) or cytotoxic T lymphocyte-associated protein-4 (CTLA-4) have achieved tumor regression in several cancers [1,2], the unexpected low response rate, typically below30%, hinders the full display of this revolutionary procedure [3]. Recent years have witnessed ever growing efforts in modulating the gut microbiome for improving responses to ICIs [4,5,6,7,8,9], through a wide variety of innovative strategies such as dietary interventions [10], administration of bacterial consortia or “Designer Probiotics” [11], and fecal microbiota transplantation (FMT) [12]. It has been well established that the increased abundance of pectin, inulin, and alike is conductive to an enhanced response to ICI treatment [16], whereas the administration of natural ingredients rich in dietary fibers is effective to modulate the gut microbiota to a favorable pattern. We demonstrated that the oral admission of jujube enriched the abundance of Lachnospiraceae while it reduced that of Prevotellaceae, thereby improving the therapeutic efficiency and response rate of anti-PD-L1 against murine colon adenocarcinoma [26]
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