Ignacio Melero
Professor of Immunology at the University of Navarra, CIMA researcher and co-director of the Department of Immunology and Immunotherapy at the Clínica Universidad de Navarra.
This is an article of extraordinary interest with far-reaching implications that go beyond cancer immunotherapy. The authors invented and have developed a method for detecting autoantibody specificities (antibodies that react with a protein produced by the body). Virtually all humans have some type of autoantibody, but this does not necessarily mean they have an autoimmune disease.
Their methodology focuses only on proteins found outside cells and therefore accessible to antibodies. They have a gene library with 3,000 of these extracellular proteins expressed on the surface of a yeast collection. By incubating human serum samples and selecting the yeasts that bind to antibodies present in the serum, the specificity of these autoantibodies can be determined. Using serum samples from cancer patients treated with immunotherapy, they find that certain autoantibodies correlate with a better response. This has important implications because it suggests that the proteins targeted by these antibodies play an important role in the escape (resistance) of the tumour to immunotherapy.
Of particular interest is the finding that type-1 interferon, an important messenger in the antiviral alarm system, appears to work against the patient, so that when autoantibodies against this substance are present, the prognosis is surprisingly improved.
Similar findings with other mediators such as TL1A are also interesting and point to new therapeutic targets using laboratory antibodies to block them. In fact, in mice transplanted with tumours, the blocking of type-1 interferons and TL1A in combination with the immunotherapies we use in patients suggests that this may indeed be the case, although the efficacy results with the treatment combinations are relatively modest.
Despite its novelty and interest, raising many questions, the work has statistical limitations that prevent it from being definitively conclusive, as the frequency with which each of these autoantibodies appears in patients is very low and a very large number of cases would be needed to have sufficient statistical power. Nor can we be sure whether autoantibodies are the factors that determine the best response to immunotherapy.
Ongoing research will resolve these uncertainties. Autoantibodies have surprising implications for human disease. For example, anti-beta-amyloid autoantibodies protect against Alzheimer's disease,
there are antibodies against folic acid receptors in the mother that determine the propensity for spina bifida in the unborn child, and autoantibodies against proteins in the immune system itself that determine susceptibility to infections such as herpes simplex virus encephalitis or tuberculosis, constituting a mechanism of immunodeficiency. This is undoubtedly an exciting field that is now linked to immunology and cancer immunotherapy.