High-throughput quantitative assessments of the chemical complementarity of celiac disease related IGH CDR3s and a gliadin epitope.

The long-term value of efficient antigen discovery includes gaining insights into the variety of potential cancer neoantigens, effective vaccines lacking adverse effects, and adaptive immune receptor (IR) targets for blocking adaptive IR-antigen interactions in autoimmunity. While the preceding goals have been partially addressed via big data approaches to HLA-epitope binding, there has been little such progress in the big data setting for adaptive IR-epitope binding. This delay in progress for the latter is likely due to, among other things, the much more complicated adaptive IR repertoire in an individual compared to individual HLA alleles. Thus, results described here represent the application of an algorithm for efficient assessment of IGH CDR3-gliadin epitope interactions, with a focus on epitopes known to be associated with an immune response in celiac disease. The hydrophobic, chemical complementarity between celiac case IGH CDR3s and known celiac epitopes was found to be greater in comparison to the hydrophobic, chemical complementarity between the same celiac case IGH CDR3s and a series of control epitopes. Thus, the approaches indicated here likely offer guidance for the development of conveniently applied algorithms for antigen verification and discovery.

Predictors of thrombosis during VV ECMO: an analysis of 9809 patients from the ELSO registry.

Venovenous extracorporeal membrane oxygenation (VV-ECMO) is a life-saving therapy for critically ill patients, but it carries an increased risk of thrombosis due to blood interacting with non-physiological surfaces. While the relationship between clinical variables and thrombosis remains unclear, our study aimed to identify which factors are most predictive of thrombosis. The Extracorporeal Life Support Organization Registry was queried to obtain a cohort of VV-ECMO patients aged 18 years and older from 2015 to 2019. Patients who were over 80-years-old, at the extremes of weight, who received less than 24 h of ECMO, multiple rounds of ECMO, or had missing data were excluded. Multivariate logistic regression modeling was used to assess predictors of thrombosis and mortality. A total of 9809 patients were included in the analysis, with a mean age of 47.1 ± 15.1 years and an average ECMO run time of 305 ± 353 h. Thrombosis occurred in 19.9% of the cohort, with circuit thrombosis (8.6%) and membrane lung failure (6.1%) being the most common. Multivariate analysis showed that ECMO runs over 14 days (OR: 2.62, P < 0.001) and pregnancy-related complications (OR: 1.79, P = 0.004) were associated with an increased risk of thrombosis. Risk factors for circuit thrombosis included incremental unit increases in the pump flow rate at 24 h (OR: 1.07 [1.00-1.14], P = 0.044) and specific cannulation sites. Increased body weight (OR: 1.02 [1.00-1.04], P = 0.026) and increased duration on ECMO (OR: 3.82 [3.12-4.71], P < 0.001) were predictive of membrane lung failure. Additionally, patients with thrombosis were at increased likelihood of in-hospital mortality (OR: 1.52, P < 0.001). This study identified multiple thrombotic risk factors in VV-ECMO, suggesting that future studies investigating the impact of pregnancy associated complications and ECMO flow rate on hemostasis would be illuminating.

IGL CDR3 Hydropathy and Antigen Chemical Complementarity Associated with Greater Disease-Free Survival in Lung Adenocarcinoma: Implications for Gender Disparities.

With lung cancer remaining a challenging disease, new approaches to biomarker discovery and therapy development are needed. Recent immunogenomics, adaptive immune receptor approaches have indicated that it is very likely that B cells play an important role in mediating better overall outcomes. As such, we assessed physicochemical features of lung adenocarcinoma resident IGL complementarity determining region-3 (CDR3) amino acid (AA) sequences and determined that hydrophobic CDR3 AA sequences were associated with a better disease-free survival (DFS) probability. Further, using a recently developed chemical complementarity scoring algorithm particularly suitable for the evaluation of large patient datasets, we determined that IGL CDR3 chemical complementarity with certain cancer testis antigens was associated with better DFS. Chemical complementarity scores for IGL CDR3-MAGEC1 represented a gender bias, with an overrepresentation of males among the higher IGL-CDR3-CTA complementarity scores that were in turn associated with better DFS (logrank p < 0.065). Overall, this study pointed towards potential biomarkers for prognoses that, in some cases are likely gender-specific; and towards biomarkers for guiding therapy, e.g., IGL-based opportunities for antigen targeting in the lung cancer setting.

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.

The presence of intratumoral Porphyromonas gingivalis correlates with a previously defined pancreatic adenocarcinoma, immune cell expression phenotype and with tumor resident, adaptive immune receptor features.

The association between pancreatic adenocarcinoma (PAAD) and the pancreatic microbiome is not fully understood, although bacteria may decrease the effectiveness of chemotherapy and lead to anti-apoptotic, pro-inflammatory microenvironments. To better understand the relationship between the PAAD microbiome and the microenvironment, we identified Porphyromonas gingivalis-positive PAAD samples and found a strong association between intratumoral P. gingivalis and: (i) an immune cell gene expression phenotype previously defined by others as gene program 7; and (ii) recovery of immunoglobulin recombination, sequencing reads. We applied a novel chemical complementarity scoring algorithm, suitable for a big data setting, and determined that the previously established P. gingivalis antigen, rpgB had a reduced chemical complementarity with T-cell receptor (TCR) complementarity-determining region-3 amino acid sequences recovered from PAAD samples with P. gingivalis in comparison to TCR-rpgB chemical complementarity represented by the PAAD samples that lacked P. gingivalis. This finding strengthens the existing body of evidence correlating P. gingivalis with PAAD, which may have implications for the treatment and prognosis of patients. Furthermore, demonstrating the correlation of P. gingivalis and gene program 7 raises the question of whether P. gingivalis infection is responsible for the gene program 7 subdivision of PAAD?

TRB CDR3 chemical complementarity with HBV epitopes correlates with increased hepatocellular carcinoma, disease-free survival.

The liver is a site of immune privilege, compared with the bladder and skin, for example. To study this attenuation of the immune response in the cancer setting, we compared quantities and features of adaptive immune receptor (IR) recombination reads obtained from hepatocellular carcinoma (HCC) and six other cancers. Of these cancers, HCC had the lowest numbers of IR recombination reads and was the only cancer with a greater number immunoglobulin rather than T-cell receptor recombination reads. To better understand the role of adaptive IRs obtained from the tumor microenvironment in shaping the outcome of HCC cases, we quantified the chemical complementarity between HCC tumor TRB and IGH complementarity determining region-3 (CDR3) amino acid (AA) sequences, and known hepatitis B virus (HBV) epitopes. High chemical complementarity between HCC-resident CDR3s and three HBV epitopes correlated with increased survival probabilities, for two sources of CDR3s representing different CDR3 recovery algorithms. These results suggest the potential of CDR3 AA sequences as biomarkers for HCC patient stratification and as guides for future development of therapeutics.

The Accumulating Deficits Model for Postoperative Mortality and Readmissions: Comparison of Four Methods Over Multiple Calendar Year Cohorts.

OBJECTIVE: To assess 4 measures of the accumulating deficits model of frailty for postoperative mortality and readmissions including their stability over time. BACKGROUND: Frailty has been assessed by multiple methods. It is unclear whether variation in how frailty is measured is important and would be stable over time. METHODS: Rockwood's 57-item frailty index was mapped onto 14,568 ICD9 diagnosis codes from Healthcare Cost and Utilization Project State Inpatient Database for the state of Florida (HCUP-SID-FL) for calendar years 2011 to 2015, inclusive, with 962 ICD9 codes matching onto 42 items. This became the modified frailty index (mFI) used. Three measures of the mFI were differentiated: the number of admission diagnoses, number of chronic conditions upon admission, and number of increased deficits accumulated during the admission. The Charlson Co-Morbidity Index was a fourth measure of frailty. The mFI of patients who survived or died and were readmitted or not were compared. RESULTS: Across all years, 4,796,006 patient observations were compared to the number of diagnoses matched on the 42 items of the mFI. The median mFI scores for each method was statistically significantly higher for patients who died compared those that survived and for patients readmitted compared to patients not readmitted for all years. There was little-to-no variation in the year to year median mFI scores. CONCLUSIONS: The 4 methods of calculating frailty performed similarly and were stable. The actual method of determining the accumulated deficits may not be as important as enumerating their number.

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

PURPOSE: Immunogenomics and earlier, pioneering studies, particularly by Whiteside and colleagues, have indicated a positive role for B-cells in breast cancer, as well as a positive role for gamma-delta T-cells. However, these studies have been completely limited to assessing breast cancer tumor tissue. METHODS AND RESULTS: Our analyses here has shown that blood-borne T-cell receptor gamma (TRG) chain sequences were associated with greater overall survival, of particular note due to the comparative longevity of primary breast cancer patients, whereby assessments of disease-free, but rarely overall survival parameters are possible. Additional immunogenomics approaches narrowed the overall survival correlations to specific, TRG complementarity determining region-3, amino acid (AA) sequence chemical features, independently of many common, confounding variables in the breast cancer setting, such as estrogen or progesterone receptor status. CONCLUSIONS: These results are discussed in the context of patient age and with regard to potential antigenic targets, based on the chemistry of the TRG CDR3 AA sequences associated with the higher survival rates.

A comparison of immune receptor recombination databases sourced from tumour exome or RNAseq files: Verifications of immunological distinctions between primary and metastatic melanoma.

It became apparent several years ago that RNAseq and exome files prepared from tissue could be mined for adaptive immune receptor (IR) recombinations, which has given extra value to datasets originally intended for gene expression or mutation studies. For example, recovery of IR recombination reads from tumour specimen genomics files can correlate with survival rates. In particular, many benchmarking processes have been applied to the two sets of the IR recombination reads obtained from the cancer genome atlas files, but these two sets have never been directly compared. Here we show that both sets largely agree regarding several parameters. For example, recovery of TRB recombination reads from both WXS and RNAseq files representing metastatic melanoma was associated with a better outcome (p < .0004 in both cases); and T-cell receptor recombination read recovery, for both genomics file types, associated very strongly with T-cell gene expression markers. However, the use of CDR3 chemical features for survival distinctions was not consistent. This topic, and the surprising result that both datasets indicated that primary melanoma with recovery of IR recombination reads, in stark contrast to metastatic melanoma, represents a worse outcome, are discussed.

Electrostatic Complementarity of T-Cell Receptor-Alpha CDR3 Domains and Mutant Amino Acids Is Associated with Better Survival Rates for Sarcomas.

While sarcoma immunology has advanced with regard to basic, and even some applied topics, this disease has not been subject to more recent immunogenomics approaches. Thus, we assessed the immune receptor recombinations available from the cancer genome atlas (TCGA) sarcoma database via tumor sample exome and RNASeq files. Results indicated that recovery of T-cell receptor-alpha recombination reads (TRA) correlated with a better survival rate, with the expression of T-cell biomarkers, and with tumor sample apoptosis signatures consistent with the longer patient survival times. Furthermore, samples representing TRA complementarity determining region-3 (CDR3) net charge per residue (NCPR) based complementarity with the corresponding sarcoma mutanome had a better survival rate, and more granzyme expression, than samples lacking such complementarity. By specifically using RNASeq-recovered TRA CDR3s and related NCPR assessments, three genes, TP53, ATRX, and RB1, were identified as being key components of the mutanome-based complementarity. Thus, these genes may represent key immune system targets for soft tissue sarcomas. Also, several key results from above were reproduced with a pediatric osteosarcoma dataset, work that led to identification of MUC6 mutations as potentially linked to a strong immune response. In sum, TRA CDR3s are likely to be important prognostic indicators, and possibly a beginning tool for immunotherapy development strategies, for adult and pediatric sarcomas.

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.

Potential MMP2-mediated availability of HLA binding, mutant ECM peptides reflects better melanoma survival rates and greater T-cell infiltrates.

Proteases in the cancer microenvironment have been studied for some time, with a general conclusion that such proteases facilitate the spread of cancer, although there is some controversy regarding that conclusion in later-stage cancer development. More recently, a very large collection of data regarding mutant amino acids in the potential substrates of cancer microenvironment proteases have become available. To better understand the potential impact of these mutant amino acids on protease function and cancer progression, we established a bioinformatics approach to assessing the impact of melanoma mutants, among a previously defined set of extracellular matrix (ECM) structural proteins, on the sensitivity of matrix metalloproteinase-2 (MMP2), extensively associated with melanoma. The results indicated that tumor samples with mutant amino acids adjacent to the ECM structural protein, MMP2 sites also represented a better survival rate and a larger proportion of mutant peptides with high HLA class I-binding affinities, particularly in comparison with melanoma samples with a reduced or absent T-cell infiltrate. Furthermore, even better HLA class I binders were identified among the samples representing the ECM structural protein mutants resistant to MMP2. Samples representing only MMP2-resistant mutants also represented a worse overall survival. Overall, this analysis suggested that MMP2 has the capacity of freeing mutant peptides that could facilitate an anti-tumor response and a better survival rate, and this analysis has the potential of resolving some of the controversy surrounding the role of cancer proteases in cancer progression.

Immune receptor recombinations from breast cancer exome files, independently and in combination with specific HLA alleles, correlate with better survival rates.

PURPOSE: Immune characterizations of cancers, including breast cancer, have led to information useful for prognoses and are considered to be important in the future of refining the use of immunotherapies, including immune checkpoint inhibitor therapies. In this study, we sought to extend these characterizations with genomics approaches, particularly with cost-effective employment of exome files. METHODS: By recovery of immune receptor recombination reads from the cancer genome atlas (TCGA) breast cancer dataset, we observed associations of these recombinations with T-cell and B-cell biomarkers and with distinct survival rates. RESULTS: Recovery of TRD or IGH recombination reads was associated with an improved disease-free survival (p = 0.047 and 0.045, respectively). Determination of the HLA types using the exome files allowed matching of T-cell receptor V- and J-gene segment usage with specific HLA alleles, in turn allowing a refinement of the association of immune receptor recombination read recoveries with survival. For example, the TRBV7, HLA-C*07:01 combination represented a significantly worse, disease-free outcome (p = 0.014) compared to all other breast cancer samples. By direct comparisons of distinct TRB gene segment usage, HLA allele combinations revealed breast cancer subgroups, within the entire TCGA breast cancer dataset with even more dramatic survival distinctions. CONCLUSIONS: In sum, the use of exome files for recovery of adaptive immune receptor recombination reads, and the simultaneous determination of HLA types, has the potential of advancing the use of immunogenomics for immune characterization of breast tumor samples.

An age-based, RNA expression paradigm for survival biomarker identification for pediatric neuroblastoma and acute lymphoblastic leukemia.

BACKGROUND: Pediatric cancer survival rates overall have been improving, but neuroblastoma (NBL) and acute lymphoblastic leukemia (ALL), two of the more prevalent pediatric cancers, remain particularly challenging. One issue not yet fully addressed is distinctions attributable to age of diagnosis. METHODS: In this report, we verified a survival difference based on diagnostic age for both pediatric NBL and pediatric ALL datasets, with younger patients surviving longer for both diseases. We identified several gene expression markers that correlated with age, along a continuum, and then used a series of age-independent survival metrics to filter these initial correlations. RESULTS: For pediatric NBL, we identified 2 genes that are expressed at a higher level in lower surviving patients with an older diagnostic age; and 4 genes that are expressed at a higher level in longer surviving patients with a younger diagnostic age. For pediatric ALL, we identified 3 genes expressed at a higher level in lower surviving patients with an older diagnostic age; and 17 genes expressed at a higher level in longer surviving patients with a younger diagnostic age. CONCLUSIONS: This process implicated pan-chromosome effects for chromosomes 11 and 17 in NBL; and for the X chromosome in ALL.

Mutant cytoskeletal and ECM peptides sensitive to the ST14 protease are associated with a worse outcome for glioblastoma multiforme.

We previously identified a set of the most frequently mutated cytoskeleton- and extracellular matrix-related proteins (CECMPs) in numerous cancer datasets. In this report, we used a bioinformatics approach to assess the impact of amino acid (AA) substitutions on the sensitivity of CECMPs to the ST14 protease (matriptase I), a transmembrane serine protease previously implicated in cancer development. Results indicated that AA substitutions in glioblastoma multiforme (GBM) CECMPs are skewed toward increased resistance to the ST14 protease, in comparison to the wild-type peptide sequence. Furthermore, the protease resistant AA substitutions represent relatively high binding affinities to HLA class I proteins, when assessing the binding specificities using HLA class I alleles matched to the source of the mutant AA. Moreover, samples representing AA substitutions that increased protease sensitivity also represented reduced overall and disease-free survival periods for patients with glioblastoma. To assess tumor specimen immunogenicity, we identified T-cell receptor (TCR) V(D)J recombinations in GBM exome files. The overlap between ST14 protease sensitive mutant barcodes and the TCR V(D)J recombination read positive barcodes represented significantly reduced survival.

Recovery of T-cell receptor V(D)J recombination reads from lower grade glioma exome files correlates with reduced survival and advanced cancer grade.

BACKGROUND: The immune system plays an important role in cancer survival and disease progression, but the role of the immune system in lower grade glioma (LGG) is largely unknown METHODS: To investigate the relationship between lymphocyte infiltration into the LGG microenvironment and LGG survival, we used a genomics approach to recover productive V(D)J recombination sequences from primary tumor, whole exome sequence files available via the cancer genome atlas RESULTS: Increased T-cell receptor V(D)J read recovery, indicating increased T-lymphocyte infiltration into the primary tumor site, strongly correlated with decreased overall and disease-free survival; and with a more advanced cancer grade. In addition, this result was more significant than related results obtainable using RNASeq-based, T-cell biomarkers, similar to a recently reported case for pancreatic cancer, where the recovery of BCR recombination reads from WXS files clearly associated with reduced survival, despite the fact that no such association was demonstrable with B-cell based, RNASeq biomarkers CONCLUSIONS: Overall, the results presented here support V(D)J recombination read recovery, from whole exome files, as a uniquely useful biomarker for distinct LGG survival rates.

IGH Complementarity Determining Region-3-Cytomegalovirus Protein Chemical Complementarity Linked to Better Overall Survival Probabilities for Glioblastoma.

Cytomegalovirus (CMV) has long been thought to have an association with glioblastoma multiforme (GBM), although the exact role of CMV and any subsequent implications for treatment have yet to be fully understood. This study addressed whether IGH complementarity determining region-3 (CDR3)-CMV protein chemical complementarity, with IGH CDR3s representing both tumor resident and blood-sourced IGH recombinations, was associated with overall survival (OS) distinctions. IGH recombination sequencing reads were obtained from (a) the Clinical Proteomic Tumor Analysis Consortium, tumor RNAseq files; and (b) the cancer genome atlas, blood exome-derived files. The Adaptive Match web tool was used to calculate chemical complementarity scores (CSs) based on hydrophobic interactions, and those scores were used to group GBM cases and assess survival probabilities. We found a higher OS probability for cases whose hydrophobic IGH CDR3-CMV protein chemical complementarity scores (Hydro CSs) were in the upper 50th percentile for several CMV proteins, including UL99 and UL123, as well as for CSs based on known B cell epitopes representing these proteins. We also identified multiple immune signature genes, including CD79A and TNFRSF17, for which higher RNA expression was associated with higher Hydro CSs. Results were consistent with the idea that stronger immunoglobulin responses to CMV are associated with better OS probabilities for GBM.

TCR CDR3-CMV Antigen Chemical Complementaries Are Associated With a Worse Outcome for Renal Cell Carcinoma.

BACKGROUND/AIM: Due to still unresolved questions regarding viruses as either a primary cause or a comorbidity in cancer, we examined a potential immune response to cytomegalovirus (CMV) in the renal cell carcinoma (RCC) setting using genomics and bioinformatics approaches. MATERIALS AND METHODS: Specifically, we assessed chemical complementarity scores (CSs) for solid tissue normal resident, T-cell receptor (TCR) complementarity determining region 3 (CDR3s) and CMV antigens and determined whether higher or lower CS groups were associated with a higher or lower survival probability. RESULTS: This was indeed the case, with all such analyses consistently indicating a lower overall and progression-free survival for the cases representing the higher TCR CDR3-CMV antigen chemical CSs. This basic result was obtained for two separate RCC datasets and multiple CMV antigens. CONCLUSION: The results raise the question, to what extent a systemic CMV infection may represent an important co-morbidity for RCC.

Specific Intratumor Bacteria Genera and TRG Recombinations Associated with Greater Survival Probability in Alimentary Tract Cancers.

INTRODUCTION: There remains a lack of knowledge regarding the effects of the intratumor microbiome on the tumor immune milieu. We aimed to investigate whether intratumoral bacterial RNA sequence abundance in gastric and esophageal cancers is associated with T-cell infiltrate features. METHODS: We assessed cases representing the stomach adenocarcinoma (STAD) and esophageal cancer (ESCA) databases of The Cancer Genome Atlas. RNA-seq data estimating intratumoral bacterial abundance was obtained from publicly available sources. TCR recombination reads were mined from exome files. Survival models were generated using the lifelines python package. RESULTS: Increasing levels of the Klebsiella genus were associated with a better OS probability (hazard ratio, 0.5), via a Cox proportional hazards model. The higher Klebsiella abundance was associated with a significantly increased overall (p = 0.0001) and disease-specific survival (p = 0.0289) probability for the STAD dataset. Cases representing the upper 50th percentile of Klebsiella abundance also represented a significantly increased recovery of TRG and TRD recombination reads (p = 0.00192). Analogous results were found for the Aquincola genus in ESCA. CONCLUSIONS: This is the first report of associations between low biomass bacterial samples from primary tumor samples with patient survival and with an increased gamma-delta T cell infiltrate. Results indicate that the gamma-delta T cells potentially play a role in the dynamics of the bacterial infiltration of primary tumors of the alimentary tract.

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.