Non-canonical proteins could be a new source of therapeutic targets to develop cancer immunotherapy treatments.
Researchers have found that some non-canonical proteins can be presented on the membrane of tumor cells and could be recognized by the patient’s T cells.
The finding was made in a study carried out by researchers from the Tumor Immunotherapy and Immunology Group of the Vall d’Hebron Institute of Oncology (VHIO), which is part of the Vall d’Hebron Campus in Barcelona.
The cells of our body have proteins in the membrane called HLA-I whose function is to present peptides derived from the degradation of intracellular proteins on the surface of the cells so that the lymphocytes or T cells recognize them as self or foreign antigens and in In this case, activate the immune response. One of the goals of immunotherapy research is to identify tumor-specific antigens that activate the immune response against the tumor, but not against healthy cells.
Using immunopeptidomic techniques, the researchers identified the peptides presented in HLA-I from nine tumor cell lines derived from patients with melanoma, gynecological cancer, and head and neck cancer. They found more than 500 peptides derived from non-canonical proteins that are candidates for being tumor antigens, that is, for being recognized by patients’ T cells and provoking an antitumor response.
“In this study we had a double objective. On the one hand, to know whether the antitumor immune response against non-canonical proteins occurred naturally in the patients and, on the other, if it is possible to select in the laboratory T cells with receptors that recognize these non-canonical peptides specifically, amplify them and use them as immunotherapy in patients” explained Dr. María Lozano, postdoctoral researcher of the VHIO Tumor Immunology Immunotherapy Group and first signatory of the study.
To determine the role of non-canonical peptides in cancer immunosurveillance, we evaluated the presence of spontaneous response of already existing T cells in the patient, targeting non-canonical tumor antigen candidates, but also other conventional candidates.
“What we observed is that while a high percentage of the conventional candidates were recognized by the patient’s T cells, none of the 507 non-canonical candidates were identified. This information is important because until now studies related to non-canonical proteins using bioinformatics tools suggested that we could find ourselves before a new source of tumor antigens as therapeutic targets that spontaneously activate the antitumor response in patients. For the moment, our results lead us to put this line of research on hold” explains Dr. Alena Gros, head of the VHIO Tumor Immunotherapy and Immunology Group.
“However” adds Dr. Gros “while it seems that we are closing one door, we are opening another, because in this same study we have been able to identify three T-cell receptors that specifically recognize three of the non-canonical peptides identified, for therefore, three new antigens and potential therapeutic targets”.
Alena Gros. (Photo: VHIO)
After selecting and amplifying the populations of T cells with these receptors in the laboratory, the next step was to verify the pattern of tumor specificity of the three candidates, since in order to develop an immunotherapy strategy it is necessary to be fully certain that the candidate peptide is not generates an immune response in the patient’s healthy tissues.
“To do this,” explains Dr. María Lozano, “we cocultivate the selected T cell populations with patient-derived tumor cell lines and with healthy cell lines. What we observed is that one of the candidate non-canonical peptides provokes the response of T cells to a greater or lesser extent in different tumor lines, but not in healthy cells, so we would be dealing with an antigen with an attractive pattern of tumor specificity. and we want to continue investigating its potential use as a therapeutic target in cancer patients”.
“We are at a very early stage and there is still a long way to go, but we have shown that there are regions of the genome that we thought were not transcribed, that are; that there are non-canonical HLA-presented proteins shared by various types of tumors and with an attractive pattern of tumor specificity; and we have identified specific T-cell receptors for these peptides” summarizes Dr. Alena Gros.
“The results of our research suggest a limited contribution of non-canonical proteins to cancer immunosurveillance, but at the same time they are a first step towards the potential use of non-canonical proteins in the development of immunotherapy strategies in cancer patients.” concludes Dr. Gros. (Source: VHIO)