At the 2022 Annual Meeting of American Association for Cancer Research (AACR), IsoPlexis presented their unique ability to connect T Cell Receptor (TCR) diversity to the most functionally potent single cells using the new Duomic™ platform. These powerful subsets of highly functional single cells are critical to driving longer term response in cell and immune therapies via functional proteins.
The presentation highlighted how connecting functional proteins and TCR repertoire at the single cell level provides a key new modality for tracking the most potent and antigen-specific immune cells together to fight cancer. This novel technique enables a wide variety of improved applications for tumor infiltrating lymphocytes (TILs), personalized neoantigen TCR’s, cancer immunology in terms of understanding antigen specificity, as well as T cell potency.
Duomic Connects TCR Repertoires and Functional Proteomics
Duomic, developed by IsoPlexis, enables simultaneous transcriptomic and highly multiplexed functional proteomic analysis from the same single cells for the first time, giving a more complete picture of how single cells function and the genetic drivers underlying those functions. The AACR presentation reveals how Duomic enables simultaneous profiling of highly multiplexed functional proteomic cytokines and TCR repertoires/TCR clonotypes as well as identification of specific TCR V(D)J recombinations with functional cell clusters across the same individual T cells.
To capture these data, cells were loaded onto IsoPlexis’ single-cell Duomic chip, which contains beads for mRNA capture. An IsoZipCode within the chip was used to link single-cell proteomic data with transcriptomic data, providing an unprecedented level of analysis from each single cell. Proteomic and transcriptomic data were analyzed using IsoSpeak software.
Duomic single-cell transcriptomics was used to sequence TCRs in T cells and characterize V(D)J usage. The top 10 most common V(D)J combinations were visualized to show the diversity of the TCR repertoire at the single-cell level. Proteomic data were then used to define three distinct cell clusters and identify the associations between the functional proteome and V(D)J distribution. The combination of these two cell attributes, measured simultaneously with Duomic, provides a new way to identify the most potent cells and the receptors facilitating specific immune response. These insights can accelerate insights into the development of precision medicine and T cell therapies, thereby improving clinical outcomes for patients.
Identifying Genetic Drivers of Cell Function
Beyond showing the link between functional proteins and TCR repertoire, IsoPlexis’ Duomic platform has been used to provide new layers of data for other research areas. Understanding the genetic drivers of cell function can provide additional insights into the development of potent and persistent cell therapies. Data presented at the 35th Annual Meeting of the Society for Immunotherapy of Cancer (SITC) further demonstrated how Duomic can be used to bridge transcriptomic and proteomic data from the same single cell. Researchers analyzed stimulated CD8+ CAR-T cells and found two distinct populations of cells defined by function, one with high polyfunctionality and the other with low polyfunctionality. Analysis of the gene expression profiles of the two cell subsets revealed that each group had a unique pattern of gene expression, highlighting the genes potentially regulating polyfunctionality and protein expression. These findings can inform the development of improved cell therapies, which can be genetically tuned to improve persistence, potency, and efficacy. This was the first time that gene regulatory networks driving critical functional protein expression in single cells were identified, demonstrating the feasibility and necessity of multi-omic analysis of individual cells.
Duomic is Redefining Single-Cell Research
These applications depict how IsoPlexis’ Duomic platform can be leveraged to improve development of cancer therapeutics. Duomic leverages IsoPlexis’ single-cell functional proteomics, described in high-impact studies as revealing key biomarkers including potency, response, efficacy, and inflammation in single cells, and adds an additional layer of transcriptomic data to delve more deeply into single-cell characterization. By linking the transcriptome and the functional proteome of each individual cell, Duomic provides next-generation insights to create more robust and precise advanced medicines and guide the manufacturing of therapies through each stage of research and development.