Williams Cancer Institute



Recent advancements in cancer treatment have seen the emergence of immune checkpoint blockade (ICB) therapy, revolutionizing the field by leveraging the immune system’s capabilities. Despite its success in certain cancers, variability in response rates and primary resistance have spurred investigations into the role of the gut microbiota in influencing antitumor immunity. This blog explores a recent study shedding light on the critical connection between gut bacteria, ICB therapy efficacy, and the promising role of specific bacterial strains.

Studies have increasingly highlighted the impact of the gut microbiota on antitumor immunity, suggesting that the composition of the intestinal microbiome could serve as a predictor for ICB therapy efficacy. Specific gut bacteria have been associated with increased antitumor immunity, offering potential avenues to address non-responsiveness to ICB therapies.

In a groundbreaking study by Lukas F. Mager et al. 2020, utilizing an animal model of colorectal cancer (CRC), researchers identified specific bacteria linked to ICB efficacy. Despite limited effectiveness of ICB therapies in CRC, treatment with anti-CTLA-4 or anti-PD-L1 antibodies resulted in significantly fewer and smaller tumors. Notably, certain bacteria, including Bifidobacterium pseudolongum and Akkermansia muciniphila, were exclusively isolated from ICB-treated tumors.

Experiments using germ-free and specific-pathogen-free mice underscored the dependence of ICB therapy efficacy on the microbiota. Anti-CTLA-4 treatment demonstrated enhanced effectiveness in specific-pathogen-free mice, emphasizing the crucial role of the microbiota. Colonization with bacteria isolated from ICB-treated tumors further confirmed the link between specific bacteria and treatment response.

Among the isolated bacterial species, B. pseudolongum, Lactobacillus johnsonii, and Olsenella species significantly enhanced anti-CTLA-4 treatment efficacy. These bacteria promoted the activation of CD4+ and CD8+ T cells, emphasizing their role in augmenting antitumor immune responses. B. pseudolongum also exhibited potential in improving the efficacy of anti-PD-L1 treatment.

The study delved into the mechanisms behind B. pseudolongum’s ability to enhance ICB therapy. Surprisingly, the bacteria’s presence within tumors was not essential for its efficacy, pointing towards soluble factors rather than direct bacterial activity. B. pseudolongum demonstrated immunomodulatory effects during homeostasis, inducing mucosal TH1 transcriptional differentiation.

Inosine, identified as a crucial bacterial-derived metabolite, played a significant role in enhancing TH1 differentiation. Context-dependent effects of inosine on TH1 cell differentiation were observed, with implications for T cell activation and effector function. The study proposed a link between gastrointestinal inflammation, compromised gut barrier integrity, and the systemic effects of B. pseudolongum during ICB therapy.

The intricate interplay between gut bacteria, metabolites, and immune responses uncovered in this study offers new avenues for manipulating the microbiota to improve the efficacy of cancer immunotherapies. Strategies altering microbiome composition or harnessing specific bacterial metabolites hold promise as potential approaches to enhance ICB therapy efficacy in cancer patients. While these findings present a compelling foundation, further studies, particularly in human subjects, are imperative to validate and translate these results into clinical practice. The study’s revelations mark a significant step towards more personalized and effective cancer treatments.

Reference: Mager, L. F., Burkhard, R., Pett, N., Cooke, N. C. A., Brown, K., Ramay, H., Paik, S., Stagg, J., Groves, R. A., Gallo, M., Lewis, I. A., Geuking, M. B., & McCoy, K. D. 13 Aug 2020. Microbiome-derived inosine modulates response to checkpoint inhibitor immunotherapy. https://doi.org/10.1126/science.abc3421

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