Checkpoint inhibitors targeting proteins such as PD-1 and CTLA-4 have revolutionized cancer treatment by restoring T-cell function and allowing the immune system to attack tumors more effectively. However, many cancers either do not respond to these treatments or develop resistance, while patients may experience immune-related severe side effects. As a result, researchers have been exploring combination therapies, including natural compounds like AHCC®, to improve treatment outcomes.
AHCC® is a standardized extract from the mycelia of Lentinula edodes (shiitake mushrooms). It has been recognized for its immune-enhancing properties, particularly in supporting T-cell and natural killer (NK) cell function. AHCC® is composed mainly of oligosaccharides, amino acids, and minerals and has been studied for its anti-cancer potential in animal models. In this study, the authors sought to investigate whether AHCC® could augment the anti-tumor effect of DICB therapy by examining tumor growth inhibition, immune cell activity, and gut microbiota changes.
In the study, C57BL/6 mice were subcutaneously inoculated with MC38 colon carcinoma cells. Three days after tumor inoculation, the mice were treated with either water or AHCC® (18 mg/mouse/day). Additionally, the treatment groups received dual immune checkpoint blockade, with anti-PD-1 (50 µg/mouse) and anti-CTLA-4 (50 µg/mouse) antibodies administered intraperitoneally twice at 3-day intervals once the tumors reached 50–100 mm³.
The combination of AHCC® and DICB significantly reduced tumor volumes compared to water and DICB. The mice treated with AHCC® and DICB exhibited smaller tumor sizes throughout the experiment, indicating an enhanced tumor-suppressive effect. Although the study does not provide specific percentages of tumor inhibition, the data suggest that AHCC® contributed to a marked tumor growth inhibition when combined with immune checkpoint therapy. This finding demonstrates the additive potential of AHCC® in improving the efficacy of immunotherapy.
The researchers further explored the impact of AHCC® on the immune response by examining the activity of tumor-infiltrating lymphocytes. Flow cytometric analysis revealed that mice treated with AHCC® and DICB exhibited increased granzyme B and Ki-67 expression in CD8+ T cells compared to those treated with water and DICB. Granzyme B is a critical cytotoxic molecule involved in T-cell-mediated tumor killing, while Ki-67 is a cell proliferation marker. These results suggest that the enhanced tumor suppression observed in the AHCC®-treated group was partly due to improved T-cell activation, proliferation, and cytotoxicity.
Interestingly, the combination treatment also affected CD4+ T cells, with increased Ki-67 expression and decreased PD-1 expression in tumor-infiltrating CD4+ T cells. The changes in CD8+ and CD4+ T cells in the AHCC®-treated mice indicate that the compound may enhance the cytotoxic and helper T-cell responses in the tumor microenvironment.
In addition to modulating immune cell activity, AHCC® appeared to influence the gut microbiome composition in treated mice. Fecal samples from the mice were analyzed for bacterial diversity, revealing an increased abundance of bacterial species from the Ruminococcaceae family in the AHCC® plus DICB group. This finding is significant because certain members of the Ruminococcaceae family have been linked to better responses to cancer immunotherapy. To further support this connection, the researchers treated some mice with antibiotics to deplete their gut microbiota. In these mice, the addition of AHCC® no longer conferred any therapeutic benefit, suggesting that the gut microbiome plays a crucial role in mediating the enhanced anti-tumor effects of AHCC®.
This study shows the potential of AHCC® as an effective adjuvant to immune checkpoint blockade therapy. The combination of AHCC® and DICB resulted in significant tumor growth inhibition, likely due to enhanced T-cell activation and changes in the gut microbiota. The study underscores the role of the gut microbiome in cancer treatment efficacy, suggesting that future studies should focus on identifying specific bacterial species involved in this response.
References
Park HJ, Boo S, Park I, Shin MS, Takahashi T, Takanari J, Homma K, Kang I. AHCC®, a Standardized Extract of Cultured Lentinula Edodes Mycelia, Promotes the Anti-Tumor Effect of Dual Immune Checkpoint Blockade Effect in Murine Colon Cancer. Front Immunol. 2022 Apr 20;13:875872. doi: 10.3389/fimmu.2022.875872. PMID: 35514996; PMCID: PMC9066372.
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