These results indicate that having a ‘fit’ microbiota helps the immune system to perform
effective immune surveillance. They also raise the questions of what a ‘fit’ microbiota
is and how we can intervene to provide the best microbiota to patients. As the diversity
of the microbiota is in part genetically determined 8], are some individuals predisposed to have a less effective microbiota, is the microbiota
shaped during tumor development, or are both of these statements true?
Interestingly, Vetizou et al. 1] show that administration of B. fragilis or Bacteroides thetaiotamicron to wild-type mice can alter the activity of anti-CTLA4 in vivo, and also reduce the
inflammatory response initiated by this antibody in the intestine. These findings
indicate that the right bacterial combination can both potentiate the activity of
ICIs and provide protection from the adverse effects of therapy, thus ‘uncoupling’
efficacy and toxicity of the antibody. The researchers also found that administration
of anti-CTLA4 modifies the microbiota composition and increases the levels of the
strains that seem to have a beneficial antitumor effect. These findings were paralleled
by observations in patients with metastatic melanoma who were treated with anti-CTLA4.
The researchers found that patients could be divided into three groups according to
their microbiota (enterotypes) and that two enterotypes were associated with a better
outcome than the other enterotype. The ‘good’ enterotypes were enriched in some, but
not other, Bacteroides species that mediate the therapeutic effect of the drug, whereas the ‘bad’ enterotype
still had quite a high number of B. fragilis, which potentiated the efficacy of anti-CTLA4 in mice. These findings suggest that
either this species is effective only in the right microbial context or that some
individuals select strains of B. fragilis that are more beneficial than others despite belonging to the same species.
It is obvious that these studies have huge therapeutic implications, but they also
raise important issues. Can we improve an individual’s microbiota to achieve maximal
therapeutic efficacy of immunotherapy? Is it sufficient to administer one species,
such as B. fragilis or B. breve, or should we give a mixture of microorganisms, or even perform fecal transplantation
of the microbiota? If two therapeutic options are available, should we select or exclude
them according to the enterotype of the patient? As chemotherapy and cytokine-based
immunotherapy also rely on the microbiota for their efficacy 9], 10], are there different enterotypes that mediate the response to different therapeutic
agents or are there enterotypes that favor any possible therapy regardless of whether
it is chemotherapy, immunotherapy or targeted therapy?
One thing is clear from these studies: the composition of our microbiota should be
considered in future clinical studies aimed at assessing the therapeutic efficacy
of new anticancer agents.