Delineation of a T-cell receptor CDR3-cancer mutanome aromaticity factor, assessable via blood samples, that facilitates the establishment of survival distinctions in bladder cancer.

A very large and still expanding collection of adaptive immune receptor (IR) recombination reads, representing many diseases, is becoming available for downstream analyses. Among the most productive approaches has been to establish risk stratification parameters via the chemical features of the IR complementarity determining region-3 (CDR3) amino acid (AA) sequences, particularly for large datasets where clinical information is available. Because the IR CDR3 AA sequences often play a large role in antigen binding, the chemistry of these AAs has the likelihood of representing a disease-related fingerprint as well as providing pre-screening information for candidate antigens. To approach this issue in a novel manner, we developed a bladder cancer, case evaluation approach based on CDR3 aromaticity. We developed and applied a simple and efficient algorithm for assessing aromatic, chemical complementarity between T-cell receptor (TCR) CDR3 AA sequences and the cancer specimen mutanome. Results indicated a survival distinction for aromatic CDR3-aromatic mutanome complementary, versus non-complementary, bladder cancer case sets. This result applied to both tumor resident and blood TCR CDR3 AA sequences and was supported by CDR3 AA sequences represented by both exome and RNAseq files. The described aromaticity factor algorithm has the potential of assisting in prognostic assessments and guiding immunotherapies for bladder cancer.

Waweru JW ，Mwangi KW ，Barker VR ，Gozlan EC ，Yeagley M ，Blanck G ，Makokha FW ... -  《-》

Immune receptor CDR3 chemical features that preserve sequence information are highly efficient in reflecting survival distinctions: A pan-cancer analysis.

Adaptive immune receptor (IR) chemical features have been used as signatures of an immune response for numerous medical conditions, raising the question of whether certain approaches to assessing the IR chemical features are more robust than others? In the cancer setting, a very large dataset of IR complementarity determining region-3 (CDR3) amino acid (AA) sequences has become available via the mining of cancer specimen and blood genomics files for IR recombination reads. The IR CDR3 AA sequences have been evaluated for chemical features, and survival rates have been correlated with distinct chemical features. Two common approaches have been i) to assign a single value to the CDR3, representing a chemical attribute, such as aromaticity; or ii) to reduce the actual CDR3 AA sequence to a chemical sequence motif, which merges similar CDR3 chemistries represented by distinct AA sequences but preserves potential functional aspects of the order of the AAs in the sequence. While a controlled comparison of the two approaches is not possible, the application of the two approaches to the same clinical datasets offers the opportunity to appreciate a trend with regard to the overall potential in distinguishing survival probabilities. We demonstrate that application of the chemical sequence motif approach is more likely to identify survival distinctions within cancer datasets, for both tumor specimen and blood sourced, adaptive IR CDR3 AA sequences.

Mcbreairty BE ，Chobrutskiy BI ，Chobrutskiy A ，Gozlan EC ，Diaz MJ ，Blanck G ... -  《-》

T-cell receptor-α CDR3 domain chemical features correlate with survival rates in bladder cancer.

Chobrutskiy BI ，Zaman S ，Diviney A ，Mihyu MM ，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 ... -  《-》

Blood-based T cell receptor anti-viral CDR3s are associated with worse overall survival for neuroblastoma.

With the advent of large collections of adaptive immune receptor recombination reads representing cancer, there is the opportunity to further investigate the adaptive immune response to viruses in the cancer setting. This is a particularly important goal due to longstanding but still not well-resolved questions about viral etiologies in cancer and viral infections as comorbidities. In this report, we assessed the T cell receptor complementarity determining region-3 (CDR3) amino acid (AA) sequences, for blood-sourced TCRs from neuroblastoma (NBL) cases, for exact AA sequence matches to previously identified anti-viral TCR CDR3 AA sequences. Results indicated the presence of anti-viral TCR CDR3 AA sequences in the NBL blood samples highly significantly correlated with worse overall survival. Furthermore, the TCR CDR3 AA sequences demonstrating chemical complementarity to many cytomegalovirus antigens represented cases with a worse outcome, including cases where such CDR3s were obtained from tumor samples. Overall, these results indicate a significant need for, and provide a novel strategy for assessing viral infection complications in NBL patients.

Kacsoh DB ，Diaz MJ ，Gozlan EC ，Sahoo A ，Song JJ ，Yeagley M ，Chobrutskiy A ，Chobrutskiy BI ，Blanck G ... -  《-》