Lessons learned about the importance of the gut microbiome composition in immune checkpoint inhibitor therapy response could be crucial in tailoring cancer care
The development of colorectal cancer (CRC) is intertwined with the microbiome – the 2 kg of microbes dispersed on the gut mucosal surfaces. Commensal organisms not only play a seminal role in the absorption of nutrients from digested food, but they also feature in the maturation of the immune system (by helping to eliminate pathogenic species), provide ‘visibility’ of food antigens to enable tolerance to certain foods, and contribute to the integrity of the epithelial barrier. CRC is linked to dysbiosis of the normal commensal gut microbiota. For instance, overgrowth of some pathogenic species and the formation of biofilms that produce metabolites, genotoxins and antigens set the stage for carcinogenesis and/or cancer metastases, particularly in the right-sided colon (Front Immunol. 2020;11:600886).
In addition to its links with CRC development, dysbiosis can also impact responses to immune checkpoint inhibitors (ICI), which are being increasingly used in the neoadjuvant and some metastatic settings. We know from the use of these therapies for other cancers, such as non-small cell lung cancer, kidney cancer, bladder cancer and melanoma, that the composition of the gut microbiome is key to response. For example, the use of antibiotics up to 2 months prior to and 42 days after immunotherapy is detrimental to the success of therapy (Nat Rev Clin Oncol. 2023;20:583–603). Research is helping to identify ways to assess the presence and extent of dysbiosis in patients with CRC and to address strategies to mitigate its effects on ICI therapy.
The identification of specific microbiome taxonomic signatures associated with positive or negative outcomes of ICI therapy across different cancer types has led to suggestions of prognostic and predictive microbiota markers. One such marker is soluble mucosal addressin cell adhesion molecule-1 (sMAdCAM-1), which is expressed by high endothelial venules of the lamina propria and is responsible for maintaining regulatory T cells in the mucosa. Intestinal dysbiosis leads to ileal downregulation of the expression of the MAdCAM-1 gene and emigration of MAdCAM-1-receptor-bearing immunosuppressive regulatory T-cells from the gut to tumours, thereby compromising both cancer immunosurveillance and the therapeutic efficacy of ICIs (Science. 2023;380:eabo2296). Analysis of sMAdCAM-1 levels in the serum of patients can be used to determine whether a patient has gut microbiome dysbiosis and, subsequently, whether they might be resistant to ICI therapy. This has been observed in patients with lung, kidney and bladder cancers, and also those with CRC.
One of the most important components of a healthy gut microbiome is Akkermansia muciniphila (Akk), which has been found to be beneficial in terms of adaptive immune responses and, along with a growing number of other species, is linked to positive outcomes to immunotherapy (Front Immunol. 2020;11:600886; Nat Rev Clin Oncol. 2023;20:583–603). Scoring of patients based on the composition of their gut microbiome – including Akk – in relation to immunotherapy outcomes (TOPOSCORE) has been associated with overall survival in some types of cancer.
This greater understanding of the gut microbiome has opened the door to a more detailed analysis of its composition and the subsequent development of biomarkers predictive of response to immunotherapy in patients with CRC. Being able to identify the patients with poor gut microbiota composition provides clinicians with the opportunity to manipulate the microbiome – for example through supplements containing beneficial species or the transplantation of faecal microbiota – and thereby potentially enhance their subsequent response to immunotherapy.
