#immunology
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Pablo Avalos Prado
Neuroscientist & Medical Writer
June 11, 2023
Microbiota impact on immune cell migration and cancer immunotherapy
A new publication in Science shows that rebounded bacteria after discontinued treatment with antibiotics impairs immunotherapy efficacy in cancer patients through relocalization of an immunosuppressive subset of cells.
In the last decade we have witnessed a boom of scientific works showing that microbiota are much more than merely residents inside our body, but also strong modulators of organ functions. In this context, gut microbiota is broadly known by regulating digestion and food absorption, production of vitamins and regulation of intestinal barrier function. But the role of these bacteria does not end here, they also play a key role in the immune system and cancer progression, as recently demonstrated by a French research group.
Cancer patients are often treated with treatments based on “immune checkpoint inhibitors” (ICI) that block tumor signals, preventing cancer from evading from immune control. In a recent publication in Science, a group of researchers have investigated why administration of antibiotics before - and not during - ICI therapy compromises the anticancer effect of this treatment. According to this work, one reason might be antibiotics misuse favoring the overgrowth of resistant intestinal bacterial species, leading to changes in biliary acids and subsequent migration of immunosuppressive cells to tumors.
Surviving microbiota after antibiotic disruption redefines T-cell migration to cancers
As cancer patients often show a weakened immune system, antibiotics are very useful to avoid potential infections during the treatment. However, antibiotics do not only target external pathogens but also internal microbiota essential for a number of body functions.
The authors demonstrated that discontinued treatment with an antibiotic cocktail of broad-spectrum (ampicillin, colistin, and streptomycin) induced re-colonization of the gut by the bacterium Enterocloster clostridioformis in mice carrying tumors. Moreover, the same treatment also downregulated the expression of the protein MAdCAM-1 in both humans and mice gut, presumably through changes in biliary acid metabolism.
MadCAM-1 is a protein expressed inside the venules of the gut that captures and “pull-out” inflammatory T-cells expressing the receptor α4ꞵ7 from the intestinal blood vessels to the gut. In the same work, the authors observed that MAdCAM-1 inhibition by E. clostridioformis leads to α4ꞵ7+ T-cell migration towards tumors, aggravating the cancer, regardless of ICI therapies. In line with this observation, restoration of MadCAM-1 by fecal microbial transplantation in mice reversed the inhibitory effects of the antibiotics. Since both E. clostridioformis supplementation and downregulation of MadCAM-1 also impaired ICI therapy, the study suggests that inhibition of MAdCAM-1 by antibiotics relocates inflammatory T-cells into tumors, compromising cancer immunosurveillance and the therapeutic efficiency of ICIs in cancer patients.
Towards cancer prediction methods based on microbiota activity
Finally, the authors explored the clinical significance of MAdCAM-1 in serum for cancer prognosis. The analysis of human tumors from 600 patients revealed that MAdCAM-1 can be used as an indicator of the microbiota status and as a robust predictor of survival of renal, bladder, and lung cancer patients under ICI immunotherapy.
Prospective studies should monitor circulating sMAdCAM-1 and α4ꞵ7+ inflammatory T-cells in cancer patients treated with ICIs alone or in combination with fecal microbial transfer to correlate these results with efficacy and toxicity.
Original article