Ultrafine Jujube Powder Enhances the Infiltration of Immune Cells during Anti-PD-L1 Treatment against Murine Colon Adenocarcinoma

Abstract

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.

Gut Microbiota-Derived Short-Chain Fatty Acids: Impact on Cancer Treatment Response and Toxicities

“…A mechanistic in vitro study in this paper showed that treatment of these cells with the SCFAs valerate and butyrate enhanced the production of CD25, IFN-γ, and TNF-α by both cytotoxic T cells and CAR T cells [ 10 ] ( Figure 2 ). A range of other in vivo studies have also shown similar results, with high-fiber diets, and subsequently increased SCFA levels, improving response to various immunotherapies [ 50 , 51 , 52 ].…”

“…In the same abovementioned ipilimumab study, authors found that in a mouse model, butyrate administration impaired anti-tumor immune response by impacting dendritic cell maturation and T cell function [ 12 ]. Another mouse study also showed that oral butyrate supplementation did not enhance anti-PD-L1 treatment, although did not decrease efficacy either [ 50 ]. These results may suggest that the efficacy of immunotherapy is not universally enhanced by increased SCFAs and may be population-dependent.…”

Sex-Biased Immune Responses to Antibiotics during Anti-PD-L1 Treatment in Mice with Colon Cancer

“…Ruff et al reported that the immune system is partially shaped by gut microbiota [ 56 ]. Peng et al showed that the abundance of Lachnospiraceae was associated with a better response to ICIs [ 30 , 35 ]. In this study, both α PD-L1 and DSS treatment reduced the abundance of Lachnospiraceae_NK4A136_group , whereas neomycin and metronidazole prominently increased it in male mice ( Figure 8(e) ).…”

“…Immune infiltration in the colon lamina propria and tumor was analyzed, as previously described [ 30 ]. In brief, the tissues (i.e., tumor and colon) were minced and digested with 1 mg/mL collagenase IV and 0.15 mg/mL DNase I in Hank's balanced salt solution at 37°C for 30 min.…”

Directing T-Cell Immune Responses for Cancer Vaccination and Immunotherapy

“…Levels of SCFA also correlate positively with anti-PD-1 responses against solid cancers [142]. A recent study testing oral administration of powder from the fruit Ziziphus jujube to mice with colon adenocarcinoma showed alteration of the gut microbiota associated with increased production of SCFA including butyrate, increases in TIL and improved responses to anti-PD-1 ICB [143]. This approach is supported by a study using pectin to improve anti-PD-1 treatment in tumour bearing mice administered FMT from CRC patients, including those resistant to anti-PD1 ICB.…”