Chemical Complementarity of Tumor Resident, Adaptive Immune Receptor CDR3s and Previously Defined Hepatitis C Virus Epitopes Correlates with Improved Outcomes in Hepatocellular Carcinoma.

To better understand how adaptive immune receptors (IRs) in hepatocellular carcinoma (HCC) microenvironments are related to disease outcomes, we employed a chemical complementarity scoring algorithm to quantify electrostatic complementarity between HCC tumor TRB or IGH complementarity-determining region 3 (CDR3) amino acid (AA) sequences and previously characterized hepatitis C virus (HCV) epitopes. High electrostatic complementarity between HCC-resident CDR3s and 12 HCV epitopes was associated with greater survival probabilities, as indicated by two distinct HCC IR CDR3 datasets. Two of the HCV epitopes, HCV*71871 (TRB) and HCV*13458 (IGH), were also determined to represent significantly larger electrostatic CDR3-HCV epitope complementarity in HCV-positive HCC cases, compared with HCV-negative HCC cases, with the CDR3s representing yet a third, independent HCC dataset. Overall, the results indicated the utility of CDR3 AA sequences as biomarkers for HCC patient stratification and as potential guides for the development of therapeutic reagents.

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.

Chemical features of melanoma tumor resident TRG CDR3s associated with better survival probabilities.

We assessed the T-cell receptor gamma (TRG) recombination reads from the cancer genome atlas melanoma tumor exome files and the TRG recombination reads from an independent, melanoma exome file dataset, from the Moffitt Cancer Center. TRG complementarity determining region-3 (CDR3) amino acid (AA) sequences were assessed for chemical complementarity to cancer testis antigens, with such complementarity for FAM133A and CRISP2 associated with better survival probabilities for both datasets. These results, along with related TRG CDR3 AA chemical feature assessments provided in this report, have indicated opportunities for melanoma patient stratifications based on the recovery of TRG recombination reads from both tumor and blood samples, and the results may point towards novel, effective melanoma antigens.

Chemical complementarity between tumor resident, T-cell receptor CDR3s and MAGEA3/6 correlates with increased melanoma survival: Potential relevance to MAGE vaccine auto-reactivity.

Cancer testis antigens have been of interest as possible targets for cancer immunotherapies. To better understand the opportunities for the use of such immunotherapy targets, we used a chemical complementarity scoring algorithm and an original web tool to establish aspects of electrostatic complementarity of the CTAs, MAGEA3 and MAGEA6, with melanoma specimen resident, T-cell receptor (TCR) complementarity determining region 3 (CDR3) amino acid sequences. Greater electrostatic complementarity between T-cell receptor CDR3 and tumor CTAs MAGEA3/6 was associated with a greater probability of overall survival, for both the cancer genome atlas and Moffitt Cancer Center samples; and was associated with high levels of T-cell cytotoxicity-related gene expression. Most importantly, this approach allowed for the highly efficient screening of specific segments of the MAGEA3/6 antigens which indicated that certain MAGE segments would have either more or less risk of auto-reactivity. In sum, the chemical complementarity algorithm, and its efficient application via the web tool, adaptivematch.com, offers a convenient opportunity to identify likely parameters important for immunotherapy considerations and melanoma patient risk stratifications.

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.

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.