The microbiome of the gut and other locations in the body may influence the development and progression of cancer and may affect the response and adverse effects from cancer therapy.
The microbiome composed of bacteria, viruses, fungi, and archaea along with their respective gnomes and secreted byproducts, such as short chain fatty acids, and other metabolites may inhabit and evolve within an individual.
The skin, G.I. tract, and respiratory tracts have distinct microbiomes that can be affected by age, geography, medications, genetic factors, disease, states, diet, and lifestyle habits.
There is a marked variability, diversity, and composition of microbial species within and between people.
Microbes interact with immune cells within the gut at the mucosal surface, gut associated lymphoid tissue and mesenteric lymph nodes.
These microbes may provide stimulator signals, such as damage associated molecular patterns, and pathogen associated molecular patterns to antigen presenting cells, which then may interact with lymphocytes and other immune cell types that alter local and systemic immune function.
Gut microbes can affect migration of immune cells from the gut into the systemic circulation by altering adhesion molecules on endothelial cells within the intestinal vasculature.
Microbial metabolites in byproducts can also circulate systemically and alter immune function.
Gut microbes can affect anti-tumor immunity as demonstrated by damaging gut epithelial integrity with drugs, checkpoint blockade, broad-spectrum antibiotics: all associated with dysbiosis and the efflux of immunosuppressive regulatory T cells from the gut altering endogenous G.I. bacteria to translocate into lymph nodes, and an impair responses to anti-cancer therapies.
Microbes within the tumor itself, can affect the development of cancer, including Helicobacteria pylori, and high risk strains of HPV.
Fecal microbiota transplant has demonstrated microbes may improve antitumor immunity, increase response to chemotherapy and increase recognition of microbioantigens by antigen specific T cells.
Antibiotics may reduce diversity of gut microbes, and negatively affect cancer outcomes.
Antibiotics in a marine model is associated with dysbiosis and decreased expression of mucosal vascular addressin cell adhesion molecule on the gut, vascular endothelium, efflux of immunosuppressive regulatory T cells from the gut and decreased efficacy of cancer immunotherapy.
Reduced levels of soluble mucosal vascular addressin cell adhesion molecule-1 with cancer is associated with dysbiosis and poor responses to immunotherapy in several different cancers types.: Including non-small cell cancer and metastatic renal cell cancer.
Studies show microbes in the gut and other anatomical locations can affect cancer therapy response, including immunotherapy, immune checkpoint blockage and stem cell transplantation, and chimeric antigen receptor T cell therapy.
Studies show a higher diversity of microbes and specific microbial tax such Akkermsnsia muciniphila, Clostridiales, Ruminococcaceae, , and Fecalibacterium species are associated with improved outcomes to treatment with immune checkpoint, blockade, and patient with melanoma, non-small cell lung, cancer and renal cell cancer. Anabiotic’s may reduce diversity of gut, microbes, and negatively affect cancer outcomes such as survival and incident of adverse events.
Several studies of patients with cancer who received board spectrum antibiotics prior to treatment with immune checkpoint blockade had low responses to chemotherapy, reduced survival and higher rates of adverse effects.
Microbial metabolites and byproducts also circulate systemically and affect immune function.
Lymphocytes that recognizes antigens on commensal organisms, could potentially recognize tumor associated antigens or tumor neoantigens, and promote anti-tumor immunity through cross reactivity between antigen’s recognized on microbes demonstrate cross reactivity to those recognized on human tumors.
Pre-clinical models have demonstrated treatment with cyclophosphamide was associated with decreased gut epithelial integrity, allowing for movement of microbes from the gut lumen into the mesentery of lymph nodes and spleen, inducing maturation of naïve CD 4 T cells into sub types with antitumor immune activity.
Gut microbes may influence response to therapy in patients with hematologic malignancies undergoing treatment with stem cell transplant or CAR T cell therapy: patient with a higher diversity of microbes within their gut and improved overall survival compared with those with a low diversity of gut microbes.
In the above studies, there was a higher relative abundance of specific microbial taxa in the gut such as Gammaproteobacteria and Enterobacteriaceae, resulting in higher mortality rates.
Higher response rates were noted when there was enrichments of Faecalbacterium, Bifidobacterium and Ruminoccocus.
Microbes within tumors have been identified such as the class of Gammaprotobacteria, in patients with pancreatic cancer, and these intra tumoral microbes may increase resistance to chemotherapy by it into inactive forms.
Microbes in addition may have inhibited bacterial growth such as F nucleator by 5FU
Microbes may mediate resistance to chemo-radiotherapy in patients with cervical cancer.
Microbiobes may influence adverse events with cancer treatments as lower diversity of gut microbiome and distinct microbial signatures is associated with high incidence of immune checkpoint blockade associated colitis, stem cell transplant graft vs host disease, increase in bacteria and vancomycin resistant enterococcus treated with broad-spectrum antibiotics, chemotherapy and radiation induced gastrointestinal adverse events.
Fecal microbiota transplant has demonstrated reversal of resistance to immune checkpoint blockade therapy, in patients with melanoma.
The G.I. microbiota may be modified by probiotic formulations, which may be composed of single microbial taxa or selected microbial communities, as well as prebiotic formulations, including indigestible food ingredients, including fiber that can promote the growth of health associated microbes in the G.I. tract.
In patients with metastatic melanoma, those who had dietary fiber intake of at least 20 g per day and a significantly longer progression free survival than patients with dietary fiber of less than 20 g per day.
Fusobacterium nucleatum is a pathogenic micro that stimulates colorectal cancer development and provokes resistance to chemotherapy in patients with colorectal cancer.
Bacteria and other microbial products, such as BCG or news for the treatment of cancer.
BCG activates both innate and adaptive antitumor immunity.
Cytokines released in response to BCG improve the immune response to cancer by recruiting and activating tumor specific immune cells.
Species of Salmonella, Clostridium, and Escherichia have been modified to reduce their ability to infect healthy cells while simultaneously stimulating the immune system and promoting antitumor immune responses.