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

Chobrutskiy, Boris I.; Chobrutskiy, Andrea; Zaman, Saif; Yeagley, Michelle; Huda, Taha I.; Blanck, George

doi:10.1016/j.molimm.2021.02.026

Cited by 30 publications

(39 citation statements)

References 24 publications

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“…However, the complementarity score (CS) calculations employed by this web tool uses a previously described approach. [ 10 ] The SOM of reference [ 10 ] contains a complete description of the calculation process along with an mp4 file showing the process in sequence. Briefly, a recovered CDR3 AA sequence is aligned with the AA sequence of a candidate antigen and a score is calculated based on the adjacency of electrostatic charges across the two sequences.…”

Section: Methodsmentioning

confidence: 99%

TCR CDR3‐antigen chemical complementarity associated with poor ovarian cancer outcomes: A vestigial immune response to early cancer antigens?

Barker

Varkhedi

Patel

et al. 2022

American J Rep Immunol

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Ovarian cancer continues to present significant challenges for early detection and treatment, indicating a need for novel approaches to improve disease outcomes. In this report, we applied a previously described algorithm for detecting chemical complementarity between candidate cancer antigens and complementarity determining region‐3 (CDR3) amino acid sequences from tumor resident T‐cell receptors. Current literature indicates an association between high CDR3‐cancer antigen complementarity and improved survival outcomes. For example, high CDR3‐BRAF electrostatic complementarity is associated with a better melanoma outcome. However, such CDR3‐cancer antigen chemical complementarity in ovarian cancer was largely associated with worse outcomes. Specifically, high CDR3‐MAGEB4 and CDR3‐TDRD1 electrostatic complementarity was associated with lower ovarian cancer disease free survival (DFS). Additionally, high CDR3‐MAGEB4 and CDR3‐TDRD1 electrostatic complementarity was associated with decreased MAGEB4/TDRD1 gene expression and gene copy numbers, consistent with a selection against ovarian cancer cells expressing these antigens. However, when TDRD1 was split into fragments, high CDR3‐TDRD1 hydrophobicity complementarity, for a specific TDRD1 fragment, was associated with increased DFS and higher immune marker expression levels. This dichotomy highlights the myriad of opportunities to establish risk stratifications and to identify potential, actionable cancer antigens using immunogenomic parameters.

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Section: Methodsmentioning

confidence: 99%

TCR CDR3‐antigen chemical complementarity associated with poor ovarian cancer outcomes: A vestigial immune response to early cancer antigens?

Barker

Varkhedi

Patel

et al. 2022

American J Rep Immunol

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“…The physicochemical characteristics of each translated complementarity determining region‐3 (CDR3) sequence for each recovered adaptive IR recombination read were assessed using methods derived from Pappu and colleagues and modified in previous projects 17–25 . (See Table S3 for all physicochemical characterizations of all CDR3s assessed in this report).…”

Section: Methodsmentioning

confidence: 99%

“…The physicochemical characteristics of each translated complementarity determining region-3 (CDR3) sequence for each recovered adaptive IR recombination read were assessed using methods derived from Pappu and colleagues and modified in previous projects. [17][18][19][20][21][22][23][24][25] (See Table S3 for all physicochemical characterizations of all CDR3s assessed in this report). Microsoft Excel pivot tables were used to obtain the mean physicochemical characteristic of the adaptive IR, CDR3 amino acid (AA) sequence collection recovered from a given, individual tumour bone marrow sample representing a case ID.…”

Section: Physicochemical Characterization Of Ir Recombination Read Co...mentioning

confidence: 99%

Exploiting adaptive immune receptor recombination read recoveries from exome files to identify subsets of ALL and to establish TCR features that correlate with better outcomes

Gozlan

Chobrutskiy

Blanck

2022

Int J Lab Hematology

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Introduction The recovery of adaptive immune receptor (IR) recombination reads from tumour‐derived genomics files has advanced the understanding of the immune system's interaction with cancer. This approach has been largely limited to solid tumours, where genomics file preparation allows for the recovery of adaptive IR reads corresponding to the T‐cells and B‐cells found in the solid tumour microenvironment. In this study, we sought to determine whether IR recombination reads from liquid tumour genomics files could also be informative. Methods We recovered the adaptive IR recombination reads from acute lymphoblastic leukaemia (ALL) normal and pathological genomics files of the Therapeutically Applicable Research to Generate Effective Treatments (TARGET)‐ALL, phase 2 project. Results In the bone marrow setting, results indicated that there was little or no B‐cell response to ALL. However, results did show survival distinctions for B‐cell ALL, in cases with specific T‐cell complementarity determining region‐3 chemical features, potentially reflecting specificity of the adaptive T‐cell response against ALL. Furthermore, we found that the B‐cell form of ALL, as well as what is likely TRD clonotypic, T‐cell ALL, could likely be diagnosed via the recovery of B‐cell receptor and TRD recombination reads, respectively, from pathological bone marrow exome files. Conclusions Recovery of IR recombination reads from ALL exomes could aid in sub‐type diagnoses and prognoses.

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“…breast cancer B-cell receptor CDR3s revealed not only a strong survival distinction when those assessments included an assessment of the chemical interaction potential of same-patient TP53 mutants but also revealed clear associations of immune markers with the higher surviving, chemical complementarity group. More recently, the chemical sequence motif approach, which preserves the presumed AA sequence functional role in the physicochemical assignments and which has already been employed in immune repertoire approaches (17), has been applied to IR CDR3s, and to CDR3-antigen matching algorithms, where the IR CDR3s have been identified in large genomics file sets (10,18). For example, an algorithm for establishing basic chemical complementarity over a large dataset of CDR3s and mutants, that employed a chemical sequence motif approach, identified correlations between TRG CDR3, AA sequence-PIK3CA mutant chemical complementarity and survival rates and immune marker expression (10).…”

Section: Immune Receptor Cdr3 Chemical Features That Preserve Sequenc...mentioning

confidence: 99%

“…More recently, the chemical sequence motif approach, which preserves the presumed AA sequence functional role in the physicochemical assignments and which has already been employed in immune repertoire approaches (17), has been applied to IR CDR3s, and to CDR3-antigen matching algorithms, where the IR CDR3s have been identified in large genomics file sets (10,18). For example, an algorithm for establishing basic chemical complementarity over a large dataset of CDR3s and mutants, that employed a chemical sequence motif approach, identified correlations between TRG CDR3, AA sequence-PIK3CA mutant chemical complementarity and survival rates and immune marker expression (10). This latter approach involved a series of alignments of mutant peptides throughout the breast cancer dataset with all of the same-patient, tumor resident TRG CDR3s, to establish in each case the highest possible chemical complementarity score indicated by the algorithm developed and employed in that report.…”

Section: Immune Receptor Cdr3 Chemical Features That Preserve Sequenc...mentioning

confidence: 99%

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

Mcbreairty

Chobrutskiy

et al. 2022

Biomed Rep

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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.

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

Cited by 30 publications

References 24 publications

TCR CDR3‐antigen chemical complementarity associated with poor ovarian cancer outcomes: A vestigial immune response to early cancer antigens?

TCR CDR3‐antigen chemical complementarity associated with poor ovarian cancer outcomes: A vestigial immune response to early cancer antigens?

Exploiting adaptive immune receptor recombination read recoveries from exome files to identify subsets of ALL and to establish TCR features that correlate with better outcomes

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

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