Molecular views of the immune system reveal opportunities for biomarker discovery
Immune Profiling in Health and Disease 2015
Seattle’s last weeks of summer brought sunshine and scientists to the inaugural Nature Conference: Immune Profiling in Health and Disease held September 9-12. Organized by Adaptive Biotechnologies and the Nature Publishing Group, the conference lived up to its profiling name with attendees discussing various methods for interrogating the immune system, generating big data, and shedding light on the molecular underpinnings of autoimmunity, vaccine effectiveness and immunotherapies. It became increasingly clear that in these fast-moving fields scientists and doctors need molecular information to understand mechanisms of action, develop prognostic indicators, and construct the most effective treatment strategies.
To obtain this information, many investigators turned toward Adaptive Biotechnologies’ high-throughput immunoSEQ® Assay for profiling T-cell and B-cell receptors (TCRs and BCRs). As evidenced by many of the presentations and posters covered during the conference, the breadth and depth at which the assay profiles the immune system makes it an attractive tool for probing immune function, assessing an immunotherapy’s potential, and monitoring the immune response to challenges.
Megan Sykes from Columbia University presented how she has used the immunoSEQ Assay to identify and track donor-reactive T cells in patients post-kidney transplantation. Sykes and colleagues determined that long-term acceptance of the donor tissue is ultimately modulated by deletion of donor-reactive T cells over the course of a few months and that identifying this deletional mechanism was impossible with other techniques . Tracking the deletion, or lack there-of, of donor specific T cells in new recipients may lead to early identification of patients with increased risk of developing host-vs-graft or graft-vs-host disease.
Stefan Gold from the Institute of Neuroimmunology and Multiple Sclerosis (INIMS) presented a poster showing early results from a study aimed at determining why mothers with relapsing-remitting multiple sclerosis have the lowest relapse rate during pregnancy than at any other time, including while under the best-known therapies . Early results are promising and suggest that not all T cells are equal with the repertoire of MS-mothers exhibiting global changes during pregnancy that do not occur in healthy mothers. Gold hopes “to use pregnancy as a window into developing personalized diagnostics and/or therapeutic for mothers with MS.”
The momentum driving the development of checkpoint inhibitors for treating various cancers also remains strong. Checkpoint inhibitors block inhibitory signals that would normally prevent T cells from attacking one’s self. Attenuating these signals in a cancerous tissue effectively removes the breaks from T cells enabling them to eradicate cancerous cells. Recent Lasker Award recipient, James Allison from MD Anderson Cancer Center, showed us that combinations of checkpoint inhibitors could bring long-term survival to more than 50% of patients with late-stage melanoma . Allison and Padmanee Sharma reminded the field that many new, understudied T-cell checkpoints are being discovered and to harness the cancer-fighting ability of the immune system fully, multiple inhibitors directed at specific, non-overlapping pathways will be required. High-throughput molecular assays that profile T-cell responses to these novel checkpoint inhibitors will be necessary to drive their development.
As the conference drew to a close, Harlan Robins, Chief Scientific Officer and Co-Founder of Adaptive, presented the pairSEQ™ Assay, a new high throughput platform for pairing the alpha and beta chains of TCRs . This capability is a game-changer in TCR profiling since it opens the door towards antigen discovery and directed engineering of highly specific TCRs. In autoimmunity, antigen discovery may lead to therapeutics that selectively wipe out offending T cells or block the interaction between TCRs and self-antigens. In immune-oncology, directed engineering of potent TCRs to target neo-antigens may deliver the final blow to immune-evading cancers. The combination of techniques to identify candidate neo-antigens [4,5], using the pairSEQ Assay to identify the entire TCR, and directed molecular engineering suggests that immunotherapies in oncology space will live up to the promise.
Dr. Robins also presented groundbreaking results strongly supporting the notion that the sequences in TCR and BCR repertoires constitute an immunological memory that can be read to diagnose pathogen infections. DeWitt et al. presented a poster which investigated the public T-cell response to CMV infection and through a bioinformatics and machine learning approach was able to diagnose CMV infection and assess HLA type based on the prevalence of certain TCRs .
Looking ahead, the future for technologies that yield unprecedented insight into the molecules underpinning T- and B-cell behavior is full of opportunities to identify public and personalized biomarkers and changing the way we diagnose, monitor and treat disease. We are looking forward to next year’s event and the exciting work researches will bring to yet another eager audience.
 Megan Sykes “Tracking the human alloresponse: a new window into tolerance and rejection” Sept. 10, 2015
 Patas et al. “T-cell repertoire shift during pregnancy as a potential mechanism for protection and from autoimmunity in humans” P19, Sept 9, 2015.
 James P. Allison “ Immune checkpoint blockade in cancer therapy: new insights and opportunities” Sept 11, 2015.
 Timothy A. Chan “Mutational Landscapes and Immunotherapy Efficacy” Sept 11, 2015
 Lélia Delamarre “Predicting immunogenic mutations for cancer and immunotherapy” Sept 11, 2015
 Harlan Robins “Immunosequencing and Cancer” Sept 11, 2015
 Howie et al. “Highthroughput pairing of T cell receptor alpha and beta sequences” Sci. Trans. Med. 2015.
 DeWitt et al. “ Immunosequencing reveals diagnostic signatures of pathogen infection and HLA type in the T cell receptor repertoire” P14, Sept. 9, 2015