High-throughput, sliding-window algorithm for assessing chemical complementarity between immune receptor CDR3 domains and cancer mutant peptides: TRG-PIK3CA interactions and breast cancer.

Physicochemical assessments of a vast accumulation of adaptive immune receptor (IR) recombinations have led to correlations of those properties with sub-divisions of various diseases. In the cancer setting, such assessments, particularly for the complementarity determining region-3 (CDR3) immune receptor domain, have been used to establish chemical complementarity matches to mutant amino acids (AA). These matches, in some cases, over very large numbers of tumor samples, have correlated with survival and gene expression distinctions. For example, in melanoma, electrostatic charge based, T-cell receptor CDR3-DNAH9 mutant AA complementarity represents better survival over multiple datasets that represent tumor tissue, T-cell receptor CDR3s. In this report, the complementarity approach has been expanded to include a more comprehensive representation of the interaction of T-cell receptor CDR3s and mutant AAs by incorporating the impact of the wild-type AAs surrounding the mutant AA. This "sliding window" approach was benchmarked against two large datasets of empirically determined CDR3-epitope pairs; showed more significant patient subdivisions; revealed a novel, TRG CDR3-mutant PIK3CA linkage in breast cancer; and was particularly suited to use with big data collections using only modest and widely-available processors. Thus, the algorithm should support more rapid and convenient indications (or prescreens) of CDR3-mutant peptide interactions for more focused studies and more efficient development of patient immunology-related prognostic tools and therapies.

Chobrutskiy BI ，Chobrutskiy A ，Zaman S ，Yeagley M ，Huda TI ，Blanck G ... -  《-》

A scoring system for the electrostatic complementarities of T-cell receptors and cancer-mutant amino acids: multi-cancer analyses of associated survival rates.

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.

Chobrutskiy BI ，Yeagley M ，Diviney A ，Zaman S ，Gozlan EC ，Tipping P ，Koohestani DM ，Roca AM ，Blanck G ... -  《-》

Chemical complementarity between immune receptor CDR3s and candidate cancer antigens correlating with reduced survival: evidence for outcome mitigation with corticosteroid treatments.

Patel AR ，Patel DN ，Tu YN ，Yeagley M ，Chobrutskiy A ，Chobrutskiy BI ，Blanck G ... -  《-》

Chemical features of melanoma tumor resident TRG CDR3s associated with better survival probabilities.

We assessed the T-cell receptor gamma (TRG) recombination reads from the cancer genome atlas melanoma tumor exome files and the TRG recombination reads from an independent, melanoma exome file dataset, from the Moffitt Cancer Center. TRG complementarity determining region-3 (CDR3) amino acid (AA) sequences were assessed for chemical complementarity to cancer testis antigens, with such complementarity for FAM133A and CRISP2 associated with better survival probabilities for both datasets. These results, along with related TRG CDR3 AA chemical feature assessments provided in this report, have indicated opportunities for melanoma patient stratifications based on the recovery of TRG recombination reads from both tumor and blood samples, and the results may point towards novel, effective melanoma antigens.

Agnila DRL ，Huda TI ，Eakins RA ，Patel DN ，Hsiang M ，Chobrutskiy A ，Chobrutskiy BI ，Blanck G ... -  《-》

Chemical features of blood-borne TRG CDR3s associated with an increased overall survival in breast cancer.

Chobrutskiy A ，Chobrutskiy BI ，Zaman S ，Hsiang M ，Blanck G ... -  《-》