Microbiome and radiotherapy: a knife that cuts two ways? - PDF Version
Suppression of local type I interferon by gut microbiota-derived butyrate impairs anti-tumour effects of ionising radiation
Yang et al, J. Exp. Med. 2021
The human microbiome has been defined as the community of microorganisms that reside in a specific environment within the human body. The host-microbiome interactions rely on a symbiotic equilibrium in which the microbiota and their metabolites play a critical role in shaping and regulating the immune system. Over the past few years, a broader picture is emerging of important connections between the microbiome, cancer development, and the efficacy of chemotherapeutic, immune-based treatments, and radiotherapy.
Recent studies in antibiotic-treated or germ-free mice have shown that the microbiome plays a key role in tumour immunity and therapy response, since it modulates both the innate and adaptive anti-tumour immune response, secretion of metabolites, and bacterial translocation to the tumour site. The connection between the gut microbiome and tumour immunity is also playing a larger role in the setting of radiotherapy, since mounting evidence shows that radiation can also stimulate an anti-tumour immune response and can be exploited to enhance anti-tumour effects in combination with immune checkpoint blockade therapy, such as anti-PD-1 immunotherapy.
Yang et al. have studied the role of the gut microbiota in the anti-tumour effects of ionising radiation (IR). They report that butyrate, which is a metabolite derived from the gut microbiota, influences tumour control after IR [1]. The oral administration of vancomycin, which decreases the abundance of butyrate-producing gut bacteria, in combination with IR improved the anti-tumour response to IR. Local administration of sodium butyrate led to a reversal in the improved IR anti-tumour response in vancomycin-treated mice. Conversely, the oral administration of Lachnospiraceae, a family of vancomycin-sensitive bacteria, was associated with increased systemic and intra-tumoural butyric acid levels and impaired the efficacy of IR in germ-free mice.
Intra-tumoural butyrate influences tumour control after IR due to inhibition of the activation of type I interferon (IFN-I) in dendritic cells within the tumour. This activation, which is mediated by the stimulator of interferon genes (STING) is required in order to activate CD8+ T-cells. Therefore, without this activation, the IR-induced, tumour-specific, cytotoxic T-cell immune response is impaired. Previous studies by Uribe-Herranz et al. show that vancomycin enhances the systemic radiotherapy-mediated anti-tumour effects by increasing antigen presentation in dendritic cells in tumour-draining lymph nodes [2]. In conclusion, these results propose that butyrate-producing bacteria and the immune-modulatory effects of butyrate, both in the systemic and intra-tumoural IR-induced tumour immunity, are potential targets to improve the clinical response to radiotherapy.
Future work must address the alterations caused by, and contributions of, other bacterial species in the tumour microenvironment of cancer patients, since these also might regulate the IR-mediated anti-tumour response. For instance, vancomycin treatment has been shown to increase levels of Akkermansia and Lactobacillus, both in the gastrointestinal tract and the tumour site. Earlier studies showed that supplementation of Akkermansia from non-responding patients to anti-PD-1 restored the efficacy of PD-1 blockade in mice by increasing levels of CD4+ T-cells [3]. The results imply that not only antibiotics and butyrate suppression can enhance immune response, but that administration of beneficial bacteria could also enhance tumour immunity. A relevant question that should be addressed is the influence of the radiation dose that was used in these studies, since a relatively high single dose of radiation was used (15-20Gy). Other studies have shown that recruitment of STING and cyclic guanosine monophosphate–adenosine monophosphate synthase (cGAS) after IR and checkpoint blockade therapy is stronger at lower fractionated doses, while at higher doses, STING activation is suppressed. In addition, radiotherapy might affect the composition of the microbiota.
There are challenges of implementation of specific microbiota or microbiota-derived metabolites as predictive biomarkers or the modulation of the gut microbiome as a therapeutic strategy. These include the complexity and heterogeneity of the microbiome among patients and the multiple environmental factors that can contribute to alterations in the microbiome composition. This fact highlights the relevance of investigating and modulating the microbiome in a patient-specific manner in order to enhance the response to cancer therapies.
In addition, there is emerging evidence that the microbiome influences the treatment outcome by modulating normal tissue toxicity. For instance, it has been suggested that vancomycin and butyrate alleviate gut-associated inflammation in IR-induced gastrointestinal toxicities, such as diarrhoea and oral mucositis. However, based on the aforementioned studies, such treatments might reduce the efficacy of IR in these cancer patients. A recent systematic analysis reviewed the key contribution of the microbiome, directly or indirectly, in the modulation of radiotherapy efficacy and radiation‐induced gastrointestinal mucositis. It provided a discussion about interventional approaches that aimed to modulate the microbiome to improve radiotherapy sensitivity and decrease normal tissue toxicity [4].
Thus, microbiome supplementation or butyrate modification may be knives that cut both ways. Notwithstanding that, the microbiome and nutritional supplementation are exciting areas of new research that will undoubtedly bring new interventions to enhance tumour radiation sensitivity and control, while preventing radiation-induced injury and/or enhancing repair of damaged tissue.
This interesting topic was discussed in depth in the interdisciplinary track “Microbiome inflammation and radiotherapy response” at the 2019 meeting of the European SocieTy for Radiotherapy and Oncology (ESTRO). At ESTRO 2021, the role of the microbiome and the radiotherapy response to it will be discussed in two fields. In the teaching lectures in the radiation biology track, it will feature under the title “The microbiome: its role in cancer development and treatment response”, and in the clinical track, it will be discussed in the talk entitled “The microbiome: an emerging concept impacting the tumour and normal tissue with implications for treatment personalisation”. Be sure to check out this topic in radiation oncology at ESTRO 2021.
Anaís Sánchez-Castillo, Kim Kampen and Marc Vooijs
Department of Radiation Oncology
GROW School for Oncology and Developmental Oncology
Maastricht University
Maastricht, The Netherlands
marc.vooijs@maastrichtuniversity.nl
Anaís Sánchez-Castillo
Kim Kampen
Marc Vooijs
References
- Yang, K.; Hou, Y.; Zhang, Y.; Liang, H.; Sharma, A.; Zheng, W.; Wang, L.; Torres, R.; Tatebe, K.; Chmura, S.J. Suppression of local type I interferon by gut microbiota–derived butyrate impairs antitumor effects of ionizing radiation. Journal of Experimental Medicine 2021, 218.
- Uribe-Herranz, M.; Rafail, S.; Beghi, S.; Gil-de-Gómez, L.; Verginadis, I.; Bittinger, K.; Pustylnikov, S.; Pierini, S.; Perales-Linares, R.; Blair, I.A. Gut microbiota modulate dendritic cell antigen presentation and radiotherapy-induced antitumor immune response. The Journal of clinical investigation 2020, 130, 466-479.
- Routy, B.; Le Chatelier, E.; Derosa, L.; Duong, C.P.; Alou, M.T.; Daillère, R.; Fluckiger, A.; Messaoudene, M.; Rauber, C.; Roberti, M.P. Gut microbiome influences efficacy of PD-1–based immunotherapy against epithelial tumors. Science 2018, 359, 91-97.
- Tonneau, M.; Elkrief, A.; Pasquier, D.; Del Socorro, T.P.; Chamaillard, M.; Bahig, H.; Routy, B. The role of the gut microbiome on radiation therapy efficacy and gastrointestinal complications: A systematic review. Radiotherapy and Oncology 2020.