Understanding immune recognition and developing cancer immunotherapy.
Human major histocompatibility complex (MHC) class I molecules present short peptides derived from endogenous proteins, to be recognised by cognate T cells. The interaction between the T cell receptor (TCR) and MHC-I forms the basis for cellular immunity and is involved in various physiological and pathological processes including immune responses against cancer. Our work focuses on understanding this interaction, as well as its regulation and modulation. We aim to exploit this knowledge to develop novel immunotherapies for cancer treatment.
Immunopeptidome and cancer-specific T cell epitopes
Peptides derived from aberrantly expressed proteins by cancer can be presented by cancer cell-expressed MHC-I molecules. The recognition of such cancer-specific peptide epitopes by cytolytic T cells leads to the elimination of cancer cells and the suppression of tumour growth. Cancer-specific peptide epitopes are a minute part of the enormous immunopeptidome presented by cancer cells, and knowing the identities of such cancer-specific peptides is key to further development of T cell-based immunotherapies such as soluble TCRs, adoptive T cell transfer, cancer peptide vaccines and TCR-mimic antibodies.
We are identifying such cancer-specific epitope peptides derived from cancer antigens including cancer testis antigens (which have restricted normal tissue expression) for future development of cancer therapy. We are using mass spectrometry and are applying techniques to enable the relative quantification of the abundance of individual peptides bound to MHC-I. We are now extending this to study epitope presentation in primary tumour samples.
Cancer immunotherapy targeting T cell epitopes: CAR-T cells
T cells play a central role in tumour immunity. Their recognition of cancer cells through binding of their TCRs with cognate MHC-I/peptide complexes are exploited in various ways to enhance the host immune response to clean up the cancer. The recent exciting development in adoptive T cell transfer field using chimeric antigen receptor (CAR)-T cells has made significant impact on leukaemia treatment. By conferring cancer specificity to in vitro expanded activated T lymphocytes through genetic engineering, the highly potent cellular response are able to be re-directed to cancer cells when transfused back to patients.
The field is rapidly expanding, and we are developing CAR-T technology using therapeutic antibodies developed in Professor Alison Banham’s group for cancer treatment in different cancer models. A category of therapeutic antibodies we are particularly interested in are the so-called TCR mimic (TCRm) antibodies, which behave similarly to TCRs by recognising MHC-I/peptide complexes but with higher affinity and better specificity.
Apart from being recognised by TCRs expressed by T cells, MHC class I molecules, as well as closely related CD1 molecules, also bind to members of multiple families of membrane proteins expressed on immune cells. Proteins such as immunoglobulin-like leucocyte receptors (LILRs) and killer cell immunoglobulin-like receptors (KIRs) – through binding to MHC-I and related molecules, along with immune checkpoint molecules – can change the course of immune responses and may contribute to induction of immune tolerance. We study the interactions between MHC-I and leucocyte receptors and their potential applications in disease control.
Dr Marloes Olde Nordkamp (Postdoc)
Hay Jung Han (DPhil student)