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

The evaluation of physicochemical characteristics of extensive adaptive immune receptor (IR) recombination sequence collections has led to the discovery of many correlations of those sequences and a variety of diseases, including cancer. In the cancer setting, these evaluations have recently focused on the adaptive IR, complementarity determining region-3 (CDR3) amino acid (AA) sequences, which play a major role in antigen binding. For example, the chemical complementarities of the tumor resident, CDR3 AA sequences and the BRAFV600E mutant, common in melanoma, have proved informative with regard to outcomes. Many of these evaluations led to the conclusion that a high affinity match, efficiently, algorithmically designated as a high chemical complementarity score (CS) for the patient specific, IR CDR3 AA sequences and the cancer antigens, correlated with improved survival outcomes. In this report, the complementarity scoring algorithms were used to investigate the opposite phenomenon, high complementarity chemistry between CRD3 AAs and cancer antigens that correlated with a worse survival, an approach that revealed potential risk stratification biomarkers for lung adenocarcinoma, lung squamous carcinoma, and likely other cancer types. Most importantly, analyses suggested that high IR CDR3 AA-candidate antigen CS, low overall survival results for low grade glioma were mitigated by neoadjuvant corticosteroid treatments. Overall, the analyses of this report, coupled with earlier work establishing the CS approach for identifying likely good outcomes, have the potential to distinguish patients who will benefit from (i) immune activating or (ii) immune augmenting or (iii) even immunosuppressive treatment strategies.Communicated by Ramaswamy H. Sarma.

Electrostatic Complementarities of Glioblastoma-Resident T-Cell Receptors and Cancer Testis Antigens Linked to Poor Outcomes and High Levels of Sphingosine Kinase-2 Expression.

INTRODUCTION: Glioblastoma (GBM) is the most aggressive primary brain tumor in adults. Despite a growing understanding of glioblastoma pathology, the prognosis remains poor. METHODS: In this study, we used a previously extensively benchmarked algorithm to retrieve immune receptor (IR) recombination reads from GBM exome files available from the cancer genome atlas. The T-cell receptor complementarity determining region-3 (CDR3) amino acid sequences that represent the IR recombination reads were assessed and used for the generation of chemical complementarity scores (CSs) that represent potential binding interactions with cancer testis antigens (CTAs), which is an approach particularly suited to a big data setting. RESULTS: The electrostatic CSs representing the TRA and TRB CDR3s and the CTAs, SPAG9, GAGE12E, and GAGE12F, indicated that an increased electrostatic CS was associated with worse disease-free survival (DFS). We also assessed the RNA expression of immune marker genes, which indicated that a high-level expression of SPHK2 and CIITA genes also correlated with high CSs and worse DFS. Furthermore, apoptosis-related gene expression was revealed to be lower when the TCR CDR3-CTA electrostatic CSs were high. CONCLUSION: Adaptive IR recombination reads from exome files have the potential to aid in GBM prognoses and may provide opportunities to detect unproductive immune responses.