ABSTRACT
The anti-tumor immune response is considered to be due to the T-cell receptor (TCR) binding to tumor antigens, which can be either wild-type, early stem cell proteins, presumably foreign to a developed immune system; or mutant peptides, foreign to the immune system because of a mutant amino acid (aa) or otherwise somatically altered aa sequence. Recently, very large numbers of TCR complementarity-determining region-3 (CDR3) aa sequences obtained from tumor specimens have become available. We developed a novel algorithm for assessing the complementarity of tumor mutant peptides and TCR CDR3s, based on the retrieval of TCR CDR3 aa sequences from both tumor specimen and patient blood exomes and by using an automated process of assessing CDR3 and mutant aa electrical charges. Results indicated many instances where high electrostatic complementarity was associated with a higher survival rate. In particular, our approach led to the identification of specific genes contributing significantly to the complementary, TCR CDR3-mutant aa. These results suggest a novel approach to tumor immunoscoring and may lead to the identification of high-priority neo-antigen, peptide vaccines; or to the identification of ex vivo stimulants of tumor-infiltrating lymphocytes.
Subject(s)
Algorithms , Antigens, Neoplasm/chemistry , Breast Neoplasms/genetics , Complementarity Determining Regions/chemistry , Lung Neoplasms/genetics , Receptor-CD3 Complex, Antigen, T-Cell/chemistry , Skin Neoplasms/genetics , Amino Acid Sequence , Amino Acids , Antigens, Neoplasm/genetics , Antigens, Neoplasm/immunology , Binding Sites , Breast Neoplasms/diagnosis , Breast Neoplasms/immunology , Breast Neoplasms/mortality , Complementarity Determining Regions/genetics , Complementarity Determining Regions/immunology , Exome , Female , Gene Expression , Humans , Lung Neoplasms/diagnosis , Lung Neoplasms/immunology , Lung Neoplasms/mortality , Male , Mutation , Prognosis , Protein Binding , Receptor-CD3 Complex, Antigen, T-Cell/genetics , Receptor-CD3 Complex, Antigen, T-Cell/immunology , Research Design , Skin Neoplasms/diagnosis , Skin Neoplasms/immunology , Skin Neoplasms/mortality , Static Electricity , Survival Rate , T-Lymphocytes/immunology , T-Lymphocytes/pathologyABSTRACT
Focusing on highly specific aspects of the immune response is likely to answer a number of basic questions, and in some cases even resolve basic contradictions, in cancer immunology. For example, there are many cases, where chronic inflammation is associated with cancer development, and many other cases where an immune response represents an anticancer process. In this study, using bioinformatics algorithms, we examined the chemical relationships between the amino acid sequences of the complementarity-determining region-3 (CDR3) represented by immune receptors associated with lower grade glioma and isocitrate dehydrogenase-1 (IDH1) mutants. In particular, we developed a chemical complementarity scoring approach to classify tumors based on the complementarity of CDR3s and mutant IDH1 amino acids, relying on net charge per residue and hydropathy parameters. There was a strong correlation between the increased survival in low-grade glioma (LGG) and complementarity of IDH1 mutants to the CDR3 domain of the T-cell receptor beta chain (TRB). Similar results were obtained for TRB CDR3s and NRAS mutants in melanoma. Furthermore, the clear connection between increased survival rates and immune receptor-IDH1 mutant complementarities may also, partially, explain the better LGG prognosis for patients with IDH1 mutants.
