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.

Eakins RA ，Chobrutskiy A ，Teer JK ，Patel DN ，Hsiang M ，Huda TI ，Zaman S ，Sexton WJ ，Coppola D ，Falasiri S ，Blanck G ，Chobrutskiy BI ... -  《-》

Chemical complementarity of tumor resident, T-cell receptor CDR3s and renalase-1 correlates with increased melanoma survival.

Zaman S ，Gorelick FS ，Chrobrutskiy A ，Chobrutskiy BI ，Desir GV ，Blanck G ... -  《Oncotarget》

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.

Agnila DRL ，Huda TI ，Eakins RA ，Patel DN ，Hsiang M ，Chobrutskiy A ，Chobrutskiy BI ，Blanck G ... -  《-》

Chemical Complementarity of Breast Cancer Resident, T-Cell Receptor CDR3 Domains and the Cancer Antigen, ARMC3, is Associated With Higher Levels of Survival and Granzyme Expression.

One of the most pressing goals for cancer immunotherapy at this time is the identification of actionable antigens. This study relies on the following considerations and approaches to identify potential breast cancer antigens: (i) the significant role of the adaptive immune receptor, complementarity determining region-3 (CDR3) in antigen binding, and the existence cancer testis antigens (CTAs); (ii) chemical attractiveness; and (iii) informing the relevance of the integration of items (i) and (ii) with patient outcome and tumor gene expression data. We have assessed CTAs for associations with survival, based on their chemical complementarity with tumor resident T-cell receptor (TCR), CDR3s. Also, we have established gene expression correlations with the high TCR CDR3-CTA chemical complementarities, for Granzyme B, and other immune biomarkers. Overall, for several independent TCR CDR3 breast cancer datasets, the CTA, ARMC3, stood out as a completely novel, candidate antigen based on multiple algorithms with highly consistent approaches. This conclusion was facilitated by use of the recently constructed Adaptive Match web tool.

Pakasticali N ，Chobrutskiy A ，Patel DN ，Hsiang M ，Zaman S ，Cios KJ ，Blanck G ，Chobrutskiy BI ... -  《-》

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.

Chobrutskiy BI ，Yeagley M ，Diviney A ，Zaman S ，Gozlan EC ，Tipping P ，Koohestani DM ，Roca AM ，Blanck G ... -  《-》