scholarly journals Enhancing Checkpoint Inhibitor Therapy in Solid Tissue Cancers: The Role of Diet, the Microbiome & Microbiome-Derived Metabolites

2021 ◽  
Vol 12 ◽  
Author(s):  
Agnieszka Beata Malczewski ◽  
Natkunam Ketheesan ◽  
Jermaine I. G. Coward ◽  
Severine Navarro

Host immunity plays a central role in the regulation of anti-tumour responses during checkpoint inhibitor therapy (CIT). The mechanisms involved in long lasting remission remain unclear. Animal studies have revealed that the microbiome influences the host immune response. This is supported by human studies linking a higher microbial richness and diversity with enhanced responses to CIT. This review focuses on the role of diet, the microbiome and the microbiome-derived metabolome in enhancing responses to current CIT in solid tissue cancers. The Western diet has been associated with dysbiosis, inflammation and numerous metabolic disorders. There is preliminary evidence that lifestyle factors including a high fibre diet are associated with improved responses to CIT via a potential effect on the microbiota. The mechanisms through which the microbiota may regulate long-term immunotherapy responses have yet to be determined, although bacterial-metabolites including short chain fatty acids (SCFAs) are recognized to have an impact on T cell differentiation, and may affect T effector/regulatory T cell balance. SCFAs were also shown to enhance the memory potential of activated CD8 T cells. Many therapeutic approaches including dietary manipulation and fecal transplantation are currently being explored in order to enhance immunotherapy responses. The microbiome-derived metabolome may be one means through which bacterial metabolic products can be monitored from the start of treatment and could be used to identify patients at risk of poor immunotherapy responses. The current review will discuss recent advances and bring together literature from related fields in nutrition, oncology and immunology to discuss possible means of modulating immunity to improve responses to current CIT.

2019 ◽  
Vol 58 (1) ◽  
pp. 18-24 ◽  
Author(s):  
Sok-Ja Janket ◽  
Leland K. Ackerson ◽  
Eleftherios P. Diamandis

Abstract As the largest immune organ, human gut microbiome could influence the efficacy of immune checkpoint inhibitor therapy (ICI). However, identifying contributory microbes from over 35,000 species is virtually impossible and the identified microbes are not consistent among studies. The reason for the disparity may be that the microbes found in feces are markers of other factors that link immune response and microbiotas. Notably, gut microbiome is influenced by stool consistency, diet and other lifestyle factors. Therefore, the ICI and microbiotas relationship must be adjusted for potential confounders and analyzed longitudinally. Moreover, a recent study where 11 low-abundance commensal bacteria induced interferon-γ-producing CD8 T cells, challenges the validity of the abundance-oriented microbiotas investigations. This study also confirmed the hierarchy in immunogenic roles among microbiotas. Fecal transplantation trials in germ-free mice provided “the proof of principle” that germ-free mice reproduce the donor’s microbiome and corresponding ICI efficacy. However, species-specific biological differences prevent direct extrapolation between the results in murine and human models. Fecal transplantation or supplementation with microbes found in ICI responders requires caution due to potential adverse events.


2019 ◽  
Vol 9 (1) ◽  
pp. 5 ◽  
Author(s):  
David Hermel ◽  
Darren Sigal

Checkpoint inhibitor therapy has introduced a revolution in contemporary anticancer therapy. It has led to dramatic improvements in patient outcomes and has spawned tremendous research into novel immunomodulatory agents and combination therapy that has changed the trajectory of cancer care. However, clinical benefit in patients with colorectal cancer has been generally limited to tumors with loss of mismatch repair function and those with specific germline mutations in the DNA polymerase gene. Unfortunately, tumors with these specific mutator phenotypes are in the minority. Recent pre-clinical and clinical studies have begun to reveal encouraging results suggesting that checkpoint inhibitor therapy can be expanded to an increasing number of colorectal tumors with microsatellite stability and the absence of traditional predictive biomarkers of checkpoint inhibitor response. These studies generally rely on combinations of checkpoint inhibitors with chemotherapy, molecular targeted therapy, radiation therapy, or other novel immunomodulatory agents. This article will review the most current data in microsatellite stable colorectal cancer.


2021 ◽  
Vol 0 (0) ◽  
pp. 0-0
Author(s):  
Abdul Rafeh Naqash ◽  
Alba J. Kihn-Alarcón ◽  
Chara Stavraka ◽  
Kathleen Kerrigan ◽  
Saman Maleki Vareki ◽  
...  

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