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.

Specific TCR V-J gene segment recombinations leading to the identification pan-V-J CDR3s associated with survival distinctions: diffuse large B-cell lymphoma.

In the diffuse large B-cell lymphoma (DLBCL) setting, we examined lymph node biopsy, T-cell receptor features, and the DLBLC patient human leukocyte antigen (HLA) alleles, to provide a basis for assessing survival distinctions represented by the National Cancer Institute Center for Cancer Research (NCICCR) dataset. While previous analyses of other cancer datasets have indicated that specific T-cell receptor (TCR) V or J gene segments, independently, can be associated with a survival distinction, we have here identified V-J recombinations, representing specific V and J gene segments associated with survival distinctions. As specific V-J recombinations represent relatively conserved complementarity determining region-3 (CDR3) amino acid sequences, we assessed the entire DLBCL NCICCR dataset for such conserved CDR3 features. Overall, this approach indicated the opportunity of identifying DLBCL patient subpopulations with TCR CDR3 features, and HLA alleles, with significant survival distinctions, possibly identifying cohorts more likely to benefit from a given immunotherapy.

TRBV and TRBJ usage, when paired with specific HLA alleles, associates with distinct head and neck cancer survival rates.

Common or dominant, T-cell receptor (TCR), V and J usage, in combination with particular human leukocyte antigen (HLA) alleles, has been associated with differing outcomes in viral infections, autoimmunity, and more recently, in cancer. Cervical cancer in particular represents the most dramatic series of distinctions of outcomes associated with differing combinations of dominant V or J usage and HLA alleles, possibly because of the strong association of cervical cancer with human papilloma virus (HPV), in turn leading to a likely molecular consistency in the mechanism of HPV antigen presentation. Thus, we considered assessing TRB V and J usage, HLA allele combinations, for their associations with survival rates and related data, in the cancer genome atlas head and neck cancer dataset. We obtained the TRB VDJ recombination reads from both the blood and tumor exome files and determined the V and J identities. We then established case ID (patient) subsets of V or J usage, HLA alleles, and determined, for example, that the TRBJ2-7, HLA-B*40:01 combination was associated with a better disease free survival rate than were either the TRBJ1-3, HLA-DPB1*03:01 or the TRBJ2-1, HLA-DPB1*02:01 combinations. Furthermore, these analyses led to the conclusion that TRBJ1-5 usage, and the HLA-C*08:02 and HLA-DRB1*03:01 alleles, had independent associations with distinct overall survival rates. In sum, the results suggest that dominant V or J usage, HLA allele combinations, and in certain cases, dominant V or J usage independently of HLA, could be useful in prognosis and in guiding immunotherapies.

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.

MMP7 sensitivity of mutant ECM proteins: An indicator of melanoma survival rates and T-cell infiltration.

OBJECTIVE: To assess the potential impact of mutant ECM amino acids (AA) on melanoma-related matrix metalloproteinase-7 (MMP7) activity. DESIGN AND METHODS: We applied a novel scripted algorithm, based on the MEROPS database, to reveal mutant-dependent sensitivity changes across the cancer genome atlas, melanoma dataset. RESULTS: This approach revealed a strong bias in favor of mutant AA dependent protease sensitivity increases. Thus, melanoma specimens with relatively few mutations had only MMP7 mutant sensitive, ECM peptides. As mutations increased, melanoma specimens included mutant AA representing mostly increased sensitivity and a small but increasing number of mutant AA representing decreased MMP7 sensitivity. There was no detection of melanoma specimens with only decreases in MMP7 sensitivity. Furthermore, melanoma specimens with exclusively increased sensitivity and thereby only a few overall mutations represented reduced T-cell infiltrates and worse outcomes. CONCLUSIONS: Overall, the results indicated that changes in MMP7 sensitivity, attributable to mutant AA, have the potential of identifying patients with distinct survival outcomes as well as patients with cancer specimen immune activity.