Antiviral T Cell Receptor Complementarity Determining Region-3 Sequences Are Associated with a Worse Cancer Outcome: A Pancancer Analysis.

Human papilloma virus has a clearly demonstrated role in cervical and head and neck cancers, but viral etiology for other solid tumors is less well understood. To expand this area of research, we obtained and analyzed the immune receptor recombinations available from both blood and tumor samples, through mining of exome files produced from those sources, for 32 cancer types represented by the cancer genome atlas (TCGA). Among TCGA data sets, the recovery frequency for antiviral complementarity determining region-3 sequences (CDR3s), for T cell receptor-alpha and T cell receptor-beta, ranged from 0% to 21% of the patients, for the different cancer types, with breast, lung, pancreatic, and thymus cancers representing the highest of that range, particularly for tumor tissue resident T cells. In several cases, recovery of the antiviral CDR3s associated with distinct survival rates, and in all of these cases, the recovery of an antiviral CDR3 associated with a worse survival rate.

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.

Chemical complementarity between immune receptor CDR3s and IDH1 mutants correlates with increased survival for lower grade glioma.

Focusing on highly specific aspects of the immune response is likely to answer a number of basic questions, and in some cases even resolve basic contradictions, in cancer immunology. For example, there are many cases, where chronic inflammation is associated with cancer development, and many other cases where an immune response represents an anticancer process. In this study, using bioinformatics algorithms, we examined the chemical relationships between the amino acid sequences of the complementarity-determining region-3 (CDR3) represented by immune receptors associated with lower grade glioma and isocitrate dehydrogenase-1 (IDH1) mutants. In particular, we developed a chemical complementarity scoring approach to classify tumors based on the complementarity of CDR3s and mutant IDH1 amino acids, relying on net charge per residue and hydropathy parameters. There was a strong correlation between the increased survival in low-grade glioma (LGG) and complementarity of IDH1 mutants to the CDR3 domain of the T-cell receptor beta chain (TRB). Similar results were obtained for TRB CDR3s and NRAS mutants in melanoma. Furthermore, the clear connection between increased survival rates and immune receptor-IDH1 mutant complementarities may also, partially, explain the better LGG prognosis for patients with IDH1 mutants.

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.

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.

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

PURPOSE: In certain cancer settings, a T-cell response to cancer represents a relatively favorable outcome. Thus, the near-future challenges include a better understanding of exactly which T-cell features contribute to a response to which cancer antigen-groups, to maximize the opportunities for tumor-infiltrating lymphocyte (TIL)-based therapies and other immunotherapies. METHODS: The immune receptor complementarity determining region-3 (CDR3) is considered to be important for antigen binding, hence, in this report, we evaluated the chemical features of the CDR3 of 846 T-cell receptor-α (TCR-α) coding regions associated with bladder tumor tissue, using bioinformatics databases. RESULTS: Results indicated that statistically significantly distinct, low value, CDR3 region isoelectric points associate with a better outcome (log rank p < 0.027, overall survival). Moreover, in samples representing the more favorable isoelectric points, known driver mutations, for example, PIK3CA (E â†’ K) with chemically complementary features overlap the better-outcome, low isoelectric point samples. Further work extended these results, i.e., survival rate-CDR3 associations, to other CDR3 chemical features and other cancers, consistent with the initial isoelectric point-related, bladder cancer findings. CONCLUSIONS: A bioinformatics assessment of cancer-associated TCR biochemical features may improve the accuracy of the predictions of which TILs will be best for ex-vivo amplification and which patients will benefit from other immunotherapies.

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.

Molecular Mechanism of Protein Kinase Recognition and Sorting by the Hsp90 Kinome-Specific Cochaperone Cdc37.

Despite the essential functions of Hsp90, little is known about the mechanism that controls substrate entry into its chaperone cycle. We show that the role of Cdc37 cochaperone reaches beyond that of an adaptor protein and find that it participates in the selective recruitment of only client kinases. Cdc37 recognizes kinase specificity determinants in both clients and nonclients and acts as a general kinase scanning factor. Kinase sorting within the client-to-nonclient continuum relies on the ability of Cdc37 to challenge the conformational stability of clients by locally unfolding them. This metastable conformational state has high affinity for Cdc37 and forms stable complexes through a multidomain cochaperone interface. The interaction with nonclients is not accompanied by conformational changes of the substrate and results in substrate dissociation. Collectively, Cdc37 performs a quality control of protein kinases, where induced conformational instability acts as a "flag" for Hsp90 dependence and stable cochaperone association.