A New Therapeutic Perspective for Colorectal Tumors: When Chemotherapy "Trains" the Immune System
A team of researchers from IFOM, the University of Turin and the University of Milan, in collaboration with Memorial Sloan Kettering Cancer Center in New York, San Raffaele Hospital and the Candiolo Institute, has identified an innovative strategy to make colorectal tumors sensitive to immunotherapy by combining two specific chemotherapeutic agents. The discovery was made possible thanks to support from the European Research Council (ERC) and the AIRC Foundation, and has been published in the prestigious scientific journal Cancer Cell, opening up new therapeutic possibilities for colorectal cancer.
Although enormous progress has been made, the lack of effective therapies still afflicts thousands of cancer patients today. Over the past 15 years, immunotherapy has represented a true revolution in oncology, increasing treatment possibilities for patients with melanoma, kidney cancer and some forms of lung cancer. However, this innovative therapy works in less than 5% of patients with metastatic colorectal cancer. This is due to the specific molecular characteristics of this type of cancer, which render it practically "invisible" to the immune system.
"For about ten years our laboratory has been studying a category of tumors with a defective DNA repair system, called mismatch repair," explains Alberto Bardelli, Scientific Director of IFOM and Full Professor in the Department of Oncology at the University of Turin, who coordinated the study.
"These tumors are defined as immune responsive," continues Giovanni Germano, IFOM Researcher and Associate Professor of Histology at the University of Milan, who coordinated the study together with Bardelli. "Due to this defect, they accumulate hundreds of mutations that create new antigens, molecules that function as 'red flags' to attract the attention of the immune system."
The goal was therefore to find a way to transform 'cold' tumors, which the immune system cannot recognise, into 'hot' tumors that can be effectively attacked. "During this experimental phase, thanks to the support of the AIRC Foundation, we discovered that drugs such as temozolomide can trigger the development of cancer cells that present those red flags that the immune system can recognise and attack more effectively," explains Bardelli. "The problem was that this approach only worked for a small subset of patients — less than 20% of those with metastatic colorectal cancer."
"Starting from these considerations, four years ago we began an innovative study," explains Pietro Paolo Vitiello, IFOM researcher and medical oncologist at the University of Turin, and first author of the study published in Cancer Cell. "We wanted to observe what would happen if we exposed tumor cells to specific combinations of chemotherapeutic agents."
The breakthrough came from studying the combination of two drugs: temozolomide, which is already known for its ability to target cells with DNA repair defects, and cisplatin. "This combination of chemotherapeutic agents induces a specific adaptive state in tumor cells," Vitiello continues. "In order to escape the destructive action of the drugs, the cells actually reduce their ability to recognise and repair DNA damage."
The tumor's defence mechanism paradoxically transforms into a vulnerability. "The cells treated with this combination began to accumulate a very high number of mutations, thus creating many new proteins," adds Germano. "This situation is similar to when bacteria or viruses invade our organism. It's as if the tumor, in attempting to protect itself from chemotherapy, has made itself recognisable and attackable by the immune system."
But the benefits don't stop there. "Thanks to our collaboration with San Raffaele Hospital," explains Vitiello, "we found that the combination of cisplatin and temozolomide can also modify the tumor microenvironment, making it more conducive to sustaining an immune response against cancer."
The research, supported by an Advanced Grant from the European Research Council's TARGET project and the AIRC Foundation, has already moved from the laboratory to the clinic. Thanks to a collaboration with Luis Diaz's group at the Memorial Sloan Kettering Cancer Center in New York, the first 18 patients have been treated with this experimental chemotherapy approach.
"The transition from the laboratory to the clinic has produced the first encouraging results," emphasises Bardelli. "Analyses of blood samples from these patients confirm that the treatment works: it effectively increases mutations in tumor cells. However," the scientist clarifies, "optimisation work is still necessary before this new therapeutic regimen can be proposed to a greater number of patients."
This discovery represents a significant paradigm shift: instead of fighting the tumor's resistance mechanisms directly, researchers have learned to exploit them. "We can think of increasingly personalised treatments," reflects Bardelli, "that guide the evolution of tumor cells towards a state that is more easily treatable with available immunological therapies."
The next step? "We will evaluate other strategies," anticipates Bardelli, "to make tumors more sensitive to immunotherapy by acting on both the production of tumor antigens and the interaction between the immune system and cancer."
"This work highlights the importance of reducing the gap between biological discoveries and clinical applications," the scientist concludes. "This result would not have been possible without the IFOM programme dedicated to physician-researchers, of which Vitiello has been an integral part since arriving at our institute. It's a programme that creates professionals with cross-disciplinary and highly translational competencies."
SCIENTIFIC BACKGROUND
The role of the mismatch repair (MMR) system
Tumors with an altered MMR system are the prototype for tumors that respond to immunotherapy. This is because, due to the altered DNA repair, these tumors accumulate hundreds of mutations that lead to the formation of new antigens: protein-derived molecules capable of attracting the attention of the immune system.
Molecular mechanism of the discovery
Adding cisplatin to temozolomide weakens the DNA repair process in tumor cells. These two chemotherapeutic agents induce numerous mutations in tumor DNA, prompting tumor cells to reduce their ability to recognise and repair DNA damage in order to escape the action of the drugs. While this adaptation temporarily protects cells from the effects of chemotherapy, it also creates a new vulnerability that can be exploited therapeutically. This makes tumors more recognisable to the immune system and more sensitive to immunotherapy.
The two chemotherapeutic protagonists
- Temozolomide: is an alkylating agent that damages tumor cell DNA by introducing specific lesions. It is effective against tumors with specific molecular characteristics and is currently mainly used in the treatment of certain brain tumors.
- Cisplatin: is a platinum-based compound that forms cross-links with DNA, preventing cellular replication. It is one of the most widely used chemotherapeutic agents in oncology for treating solid tumors, such as those of the testicle, ovary, bladder and lung.
Tumor microenvironment modifications
Tumors consist of tumor cells and other cells in the surrounding tissue, such as immune cells, which constitute the so-called "tumor microenvironment." The combination of cisplatin and temozolomide can modify the characteristics of cells in the tumor microenvironment, enhancing elements that support immune activation against the tumor.