Colorectal cancer, the search for a new cure begins

It is an extremely promising treatment option for many tumor pathologiesbut in the case of tumor of colon rectumwhich represents the second cause of death for oncological reasons worldwide, the use ofimmunotherapy is severely limited today. This is because in most cases – equal to about 95% of metastatic patients – colon cancers are immunologically “cold”that is to say refractory to immunotherapy, and only 5% are “hot” tumors able to benefit from these innovative treatments. The difference is probably due to the DNA repair mechanisms and more precisely to what scientists call mismatch repair (mmr).

“In approximately 95% of patients with metastatic colorectal cancer – explains Alberto Bardelli, director of the Ifom research program Tumor genomics and targeted anticancer therapies and full professor at the University of Turin – this repair mechanism is intact and functional. Therefore these tumors result immunologically cold and refractory to immunotherapy with immune checkpoint inhibitors. Only in the rest about 5% of patients the tumor has lost this repair mechanism of the DNA and, consequently, is characterized by a high production of altered proteins which are called in jargon neoantigens. Such proteins attract cells of the immune system making the tumor effectively treatable with immunotherapy”.

“Two years ago – explains Vito Amodio, researcher of Ifom, University of Turin and Istituto di Candiolo Irccs – we wondered if it was possible increase the percentage of patients that they can benefit from immunotherapy identifying those cold tumors that inside they hide a warm component”. This study went precisely in this direction, again conducted by Bardelli and his group at the Ifom in Milan and at the University of Turin with the support of the Airc Foundation. “We found out that in the small group of heterogeneous tumors for the status of the Mr – continues Amodio, first author of the article and holder of an Airc scholarship -, potentially cold and warm tumor areas coexist from an immunological point of view. We wondered if there were therapies already available able to increase the efficacy of immunotherapy for colorectal cancers that do not currently benefit from it”.

Researchers have studied this condition in the laboratory molecular heterogeneity Which potential target to act on transform cold and refractory tumors to the immune system in warm tumors and able to respond to immunotherapy. The encouraging results obtained were published in the scientific journal Cancer cell, which also dedicated the cover of the newspaper to the study. “We designed special experiments, in laboratory mice in which it was possible to reproduce at least in part the disease observed in the patients – says Giovanni Germano, researcher of Ifom, University of Turin and Istituto di Candiolo Irccs and co-author of the article alongside Bardelli -. Thanks to the use of techniques of molecular biology and of bioinformatic analyses we discovered such as the portion of cells with an altered Mmr may activate an effective immune response even against the counterpart characterized by a functioning MMR”.