Deciphering the interactions between the immune system and cancer cells to enable precision medicine
Creators: name: Serra, Victoria Isabel Ruiz
name: Valencia, Alfonso
name: Porta-Pardo, Eduard
Publisher: name: F1000 Research Limited
Year: 2019

description: Every year, the worldwide incidence of cancer increases. Over 18 million people were diagnosed in 2018 alone and half of them are estimated to die from this disease. Part of this problem comes from the insufficient effectivity of standard treatments. Current research focuses on the development of strategies for treating those cancer types where other approaches fail. In this sense, the most promising next generation of cancer treatments are immunotherapies. Their advantage lies in the physiological cell-mediated immune response specificity when targeting tumor cells. So far, its effectiveness has been proven in cancer types where the standard treatments fail, such as metastatic lung cancer, metastatic melanoma and some blood cancers.<br><br>Although immunotherapies are a breakthrough in cancer medicine they are still limited to a subset of patients presenting certain clinical characteristics. Understanding the complexity of the intratumoral immune response will suppose a step closer to their complete success. Besides, we need a better insight on how the tumor-immune interaction network is affected by the accumulation of somatic cancer mutations.<br><br>Against the general tendency to study the effect of cancer-associated somatic mutations on a gene level, the present work pays attention to their impact on the immunological tumor microenvironment (TME) from a structural point of view. For instance, it is not the same to find a mutation affecting the catalytic site of a protein than in a non-functional area of the structure. We hypothesized that cancer-associated mutations involved in interaction areas or interfaces will provide a more comprehensive picture of why certain tumors have immune privilege. Our aim is to complement the gene-centered view of cancer.<br><br>To identify such interfaces, we analyzed more than 200.000 protein coordinate files from the Protein Data Bank. We defined protein interfaces as all the residues in close proximity (≤ 5Å) to either other proteins, nucleic acids or small ligands. We then used a linear model to describe the relationship between the location of missense somatic mutations from 10224 patients from The Cancer Genome Atlas and their tumor immune infiltration levels.<br><br>Our preliminary results show that 13379 of these interfaces, when somatically mutated, correlate with changes in the quantity of the immune infiltrate in the TME. Some hits correspond to typical cancer-associated genes such as CASP8, IDH1, or KRAS, where we are able to go beyond gene-centric analyses and distinguish different immune-effects depending on the region of the protein mutated. A less known example involves mutations on the interface between PAD1 and Ca2+ atoms, catalytic site of the enzyme. Patients with this interface mutated correlate with higher levels of immune infiltrate compare to mutations in other part of the protein or a wild type phenotype for that gene. Since PAD1 is in charge of protein citrullination, source of antigenic epitopes, perhaps a malfunctioning of its catalytic site could lead to the evasion of the immune system.<br><br>In summary, the analysis of individual protein interfaces provides valuable information to improve the understanding of the relationship between cancer cells and the TME.