Enhancing the Efficacy of Melanoma Immunotherapy with Lactobacillus reuteri

The Role of Probiotics in Melanoma Treatment

The use of probiotics by cancer patients, especially those undergoing immune checkpoint inhibitor (ICI) therapy, is on the rise. Recent studies on mice with melanoma indicate that probiotics can migrate from the gut and establish themselves within the tumor, thereby directly stimulating immune cells and augmenting the efficacy of cancer immunotherapy.

One specific strain, Lactobacillus reuteri, has been found to stimulate the function of killer T cells by producing a compound called indole-3-aldehyde (I3A). When the mice were fed a diet rich in tryptophan, an amino acid that L. reuteri converts into I3A, immunotherapy drugs showed an enhanced efficacy in reducing tumor size and extending mice's survival rate.

Interaction of Lactobacillus reuteri with Immune Cells in Tumor

Gut microbes are known to affect immune therapy response. However, more clarity is needed on how this happens and whether these microbes need to be present in the tumor site to exert a positive effect. Studies reveal that orally administered L. reuteri could effectively facilitate the migration of bacteria to tumorous regions beyond the gut. There, bacteria directly influence immune cells in the tumor, enhancing the effectiveness of cancer immunotherapy.

For further exploration, researchers administered L. reuteri to germ-free mice with melanoma, a strain that is generally found in commercially available probiotics. The findings revealed that L. reuteri could transition from the gut to the tumor, establishing a long-term presence. Compared to the control group of mice that did not receive the bacteria, the mice treated with L. reuteri had more functional CD8+ T cells in the tumor, which caused significant tumor shrinkage and extended life expectancy. Notably, the impact of L. reuteri was not confined to melanoma; it was also effective in moving to extraintestinal tumors in adenoma, fibroma, and breast cancer mouse models, thereby inhibiting cancer growth.

Fig.1 Molecular mechanism of probiotics enhancing response to melanoma immunotherapy.¹

I3A: A Key Player in Strengthening Immune Therapy Response

Further research disclosed that L. reuteri could stimulate tumor immunity by producing I3A, which activates receptors in CD8 cells. Although these receptors are present in almost all body cells, I3A specifically enhances the body's ability to combat cancer by targeting CD8 cells. If these receptors were removed from the cells, the bacteria would no longer induce anti-tumor immunity in the body. This suggests that the therapeutic efficacy of L. reuteri is dependent on the interaction of I3A with CD8+ T cells.

It is worth noting that while tumor microbiomes outside the gut, including melanoma, have been discussed, the concept of tumor microbiomes playing a proactive role in mediating cancer immunotherapy has not been elucidated. Therefore, it came as a surprising revelation that I3A produced by L. reuteri in tumors could enhance immune therapy response. Yet, the presence of L. reuteri in the gut alone was not sufficient to produce tangible anti-tumor effects.

High pre-therapy levels of I3A in the body might be associated with better survival chances for patients undergoing immune checkpoint inhibitor therapy for melanoma. It is hoped that future research will utilize I3A levels as a biomarker to predict which patients would most likely respond to immunotherapy. The findings may pave the way for clinical trials to assess whether I3A therapy or a combination of probiotics and diet could improve the therapy outcome for melanoma patients undergoing immunotherapy.

Creative Biolabs has rich professional experience in discovering next-generation probiotics targeting different diseases. Please contact us for more information.

Reference

1. Bender, Mackenzie J., et al. "Dietary tryptophan metabolite released by intratumoral Lactobacillus reuteri facilitates immune checkpoint inhibitor treatment." Cell 186.9 (2023): 1846-1862.

For Research Use Only. Not intended for use in food manufacturing or medical procedures (diagnostics or therapeutics). Do Not Use in Humans.