Every individual harbours a vast and unique repertoire of immune receptors (T-cell receptors and B-cell receptors) which discriminate, at the molecular level, self from non-self. The structural diversity of the T-cell receptor (TCR) that is necessary for recognizing diverse antigens is generated mainly by stochastic shuffling of the large number of short DNA segments that comprise TCR genes. Although the central importance of T cells in adaptive immunity has been well established for decades, the actual number and diversity of T cells that exist in an individual (i.e. the T-cell repertoire), how this changes in response to immune challenge, and how it varies from one individual to the next has remained unknown, and subject to much speculation. We applied deep sequencing to T-cell repertoire analysis to obtain a first glimpse of repertoire diversity at the ultimate resolution of individual clonotypes (Freeman et al., Genome Research 2009). Currently, we are using these methods to explore the role of T cells in cancer, and how to enhance the anti-cancer immune response. We are particularly focussed on developing new sequence and informatics based approaches to T cell antigen discovery and characterization.
It has been recognized for nearly three decades that patients with tumors that are strongly infiltrated by T-cells, in particular cytotoxic T cells, have better outcomes. We use computational approaches and targeted immuno-assays in the lab to gain insights into the nature of the anti-cancer T cell response, and to determine how and why it varies among healthy individuals and among cancer patients. These studies inform our programs for pre-clinical and clinical development of genetically engineered T cell therapies, including Chimeric Antigen Receptor (CAR-T) and Recombinant T cell Receptor (rTCR) therapies for cancer.
We are particularly focussed on using rTCRs to target cancer hotspot mutations. These are mutations that are seen in certain cancers at high frequency, which is unusual because most cancer mutations are random. We are systematically assessing hotspot mutations for their immunogenicity using a combination of genomics, mass spectrometry, flow cytometry and cellular immunoassays. We are optimizing procedures of isolating, expanding, activating, and redelivering these mutation-reactive T cells as targeted immunotherapies
A substantial proportion (at least 15%) of the global cancer burden is attributable to known infectious agents, such as HPV, HBV and H.pylori. It is possible that infectious agents may have a still greater role in cancer etiology, but traditional methods for finding them have limited sensitivity. We find pathogens by their sequence signatures in human tissues, using genomic methods. Our application of these methods to colorectal carcinoma identified a strong link to the emerging pathogen Fusobacterium nucleatum (Castellarin et al., Genome Research 2011). Currently, as part of the Cancer Research UK OPTIMISTICC Grand Challenge program we are characterizing the host immune response to F. nucleatum and other oncomicrobes, to inform vaccine development.