Exploiting big data survival information to unify risk-stratification related, adaptive immune receptor parameters for multiple myeloma.

With the improvement of treatment options, multiple myeloma related life expectancy has been prolonged, but the disease remains largely incurable. Immunotherapy is a growing field that shows promise in advancements for treatment, and recent work has demonstrated an opportunity to use immune receptor, complementarity determining region-3 (CDR3)-candidate antigen chemical complementarity scores to identify survival distinctions among subgroups of patients. Here, we have applied the complementarity scoring algorithm to identify multiple myeloma related, CDR3-cancer testis antigen (CTA) relationships associated with survival distinctions. Furthermore, we have overlapped these immune receptor features with a previous study that showed a dramatic survival distinction based on T-cell receptor, V- and J-gene segment usage, HLA allele combinations, whereby 100% of the patients in certain combination groups had no mortality related to multiple myeloma, during the study period. This overlap evaluation was consistent with the idea that there are likely considerable constraints on productive TRB-antigen-HLA combinations but more flexibility, and unpredictability, for the TRA-antigen-HLA combinations. Also, the approaches in this reported indicated the potential importance of the CTA, IGSF11, as a multiple myeloma antigen, an antigen previously, independently considered as a vaccine candidate in other settings.

Surgical Management of the Axilla in HR+/HER2- Breast Cancer in the Z1071 Era: A Propensity Score-Matched Analysis of the National Cancer Database.

BACKGROUND: Axillary management varies between sentinel lymph node biopsy (SLNB) and axillary lymph node dissection (ALND) for patients with clinical N1 (cN1), hormone receptor-positive (HR+), human epidermal growth factor receptor 2 (HER2)/neu-negative (HER2-), infiltrative ductal carcinoma (IDC) who achieve a complete clinical response (cCR) to neoadjuvant systemic therapy (NAST). This study sought to evaluate clinical practice patterns and survival outcomes of SLNB versus ALND in this patient subset. METHODS: Patients with cN1, HR+/HER2-, unilateral IDC demonstrating a cCR to NAST were identified from the 2012-2017 National Cancer Database (NCDB) and stratified based on final axillary surgery management (SLNB vs ALND). After propensity score-matching, overall survival (OS) was compared using a Kaplan-Meier analysis, and significant OS predictors were identified using Cox regression. RESULTS: Of the 1676 patients selected for this study, 593 (35.4%) underwent SLNB and 1083 (64.6%) underwent ALND. Use of SLNB increased by 28 % between 2012 and 2017. Among a total of 584 matched patients, 461 matched ypN0 patients, and 108 matched ypN+ patients, mean OS did not differ between SLNB and ALND (all patients [92.1 ± 0.8 vs 90.2 ± 1.0 months; p = 0.157], ypN0 patients [92.4 ± 0.8 vs 89.9 ± 0.9 months; p = 0.105], ypN+ patients [83.5 ± 2.3 vs 91.7 ± 2.7 months; p ± 0.963). Cox regression identified age, Charlson score, clinical T stage, and pathologic nodal status as significant predictors of OS. CONCLUSION: The final surgical management strategy used for cN1, HR+/HER2- IDC patients who achieved a cCR to NAST did not have a significant impact on survival outcomes in this analysis. Potential opportunities for de-escalation of axillary management among this patient subset exist, and validation studies are needed.

TCR gene segment usage and HLA alleles that are associated with cancer survival rates also represent racial disparities.

Understanding racial disparities in cancer outcomes continues to be a challenge, with likely many factors at play, including socioeconomic factors and genetic polymorphisms impacting basic cellular and molecular functions. Additionally, it is possible that specific combinations of environment and genetics have specific impacts. T-cell receptor (TCR) gene segment usage, HLA allele combinations have been associated with autoimmune and infectious disease courses, and more recently, TCR gene segment usage, HLA allele combinations have been associated with distinct survival outcomes in cancer as well. We examined several such, previously reported cancer-related TCR gene segment usage, HLA allele combinations for evidence of racial disparities, with regard to the prevalence of the combination in different racial groups. Results indicated that TCR gene segment usage, potentially reflecting environmental factors related to previous pathogen exposure, in combination with certain HLA alleles or independently, may represent a novel explanation for racial disparities in cancer outcomes. Overall, at this point, a genetic connection to racial disparities in cancer outcomes is detectable but remains modest, suggesting that other factors, such as socioeconomic factors, remain as important considerations.

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

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.

TRB CDR3-cancer testis antigen chemical complementarity scoring for identifying productive immune responses in renal cell carcinoma.

BACKGROUND: Immunogenomics approaches to the characterization of renal cell carcinoma (RCC) have helped to better our understanding of the features of RCC immune dysfunction. However, much is still unknown with regard to specific immune interactions and their impact in the tumor microenvironment. OBJECTIVE: This study applied chemical complementarity scoring for the TRB complementarity determining region-3 (CDR3) amino acid sequences and cancer testis antigens (CTAs) to determine whether such complementarity correlated with survival and the expression of immune marker genes. METHODS: TRB recombination reads from RCC tumor samples from RNAseq files obtained from two separate databases, Moffitt Cancer Center and The Cancer Genome Atlas (TCGA), were evaluated. Chemical complementarity scores (CSs) were calculated for TRB CDR3-CTA pairs and survival assessments based on those CSs were performed. RESULTS: Moffitt Cancer Center and TCGA cases representing the upper 50th percentile of chemical CSs for TRB CDR3 amino acid sequences and the CTA POTEA were found to be associated with a better overall survival (OS) Also, greater tumor RNA expression of multiple immune signature genes, including granzyme A, granzyme B, and interferon-gamma were correlated with the higher chemical CSs. CONCLUSIONS: These results indicate that TRB CDR3-CTA chemical complementarity scoring may be useful in distinguishing RCC cases with a productive, anti-tumor immune response from cases where basic immune parameter assessments are inconsistent with a productive immune response.

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.

PURPOSE: 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. METHODS: 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: 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. CONCLUSION: The described aromaticity factor algorithm has the potential of assisting in prognostic assessments and guiding immunotherapies for bladder cancer.

An immunoinformatics assessment of the cancer testis antigen, DDX53, as a potential early esophageal cancer antigen.

T-lymphocytes have been implicated in facilitating a pro-inflammatory, pro-tumorigenic microenvironment that worsens prognosis for esophageal carcinoma (ESCA). In this study, we identified tumor resident, T-cell receptor (TCR) complementarity determining region-3 (CDR3) amino acid sequences and employed an algorithm particularly suited to the big data setting to evaluate TCR CDR3-cancer testis antigen (CTA) chemical complementarities. Chemical complementarity of the ESCA TCR CDR3s and the cancer testis antigen DDX53 represented a disease-free survival (DFS) distinction, whereby the upper fiftieth percentile complementarity group correlated with worse DFS. The high TCR CDR3-DDX53 complementarity group also represented a greater proportion of tumor samples lacking DDX53 expression. These data and analyses raise the question of whether the TCR CDR3-DDX53 chemical complementarity assessment detected an ESCA immune response that selected for DDX53-negative cells?

CNV assessments associated with outcome distinctions for adult and pediatric cancers: Loss of BRCA1 in neuroblastoma associates with a lower survival probability.

DNA copy number variations (CNV) are common in cancer development, however, CNV detection approaches that include assessments of small CNVs, for example, due to locally misaligned sister chromatid exchanges, have not been substantially applied. Using such approaches, CNVs have been detected, in the cancer setting, for regulatory elements common to both proliferation and apoptosis effector genes, but no linkage has yet been made to cancer patient clinical data. Thus, we hypothesized that copy number losses, including local copy number losses, of specific apoptosis effector genes would be associated with reduced survival. Both whole genome and whole exome files were processed for validations and consistency. Results indicated lower late-stage survival for multiple myeloma cases representing reduced BAD and CASP3 copies, as well as for lung adenocarcinoma cases representing reduced BAX and CASP3 copies. Results also indicated that neuroblastoma (NBL) cases representing reduced copies of CASP9 and BRCA1 had reduced overall survival probabilities, with the BRCA1 results being particularly notable due to previous reports of BRCA1 inactivating mutations in NBL. Overall, novel approaches to assessing CNVs offers the promise of establishing patient risk stratifications and of identifying single genes or other small spaces in the genome where a CNV may be linked to specific outcomes.