Award Title: AN ANALYSIS OF PEPTIDE TRAFFICKING AND THE ANTI-TUMOUR IMMUNE RESPONSE IN THE CONTEXT OF IMMUNOTHERAPY IN COLORECTAL CANCER
Funder: The Academy of Medical Sciences

Abstract: Long-term responses to immunotherapy in colorectal cancer patients are variable and poorly understood. The aims of this project are (1) to set up and analyse two new clinical immunotherapy cohorts of CRC patients, (2) elicit the relative importance of tumour biology and host immune response in determining the response to immunotherapy, focussing on intracellular peptide trafficking via golgi vesicle formation and exocytosis, (3) identify the mechanisms of how gene expression changes of these candidate genes/genesets alter tumour profiles or immune cell responses and other aspects of the tumour microenvironment.

Immunogenomic approaches, using whole transcriptomic analyses, have recently been developed as a strategy to simultaneously understand tumour biology and the anti-cancer immune responses. There are potential benefits as it allows a quantification of immune cell subtypes in the tumour and their relative levels of activation. From a cancer cell perspective, it enables an accurate measurement of cellular phenotypes, not possible from other techniques. 

My pilot work has identified that abnormal peptide trafficking following cell proteasome activity links tumour biology to the degree of immune activation. Lower levels of cellular peptide trafficking by the golgi apparatus and vesicle exocytosis lead to poorer immune initiation, through decreased tumour antigen presentation on MHC complexes. 

These changes in cellular peptide trafficking potentially enable a tumour to inhibit immune initiation and thereby become resistant to immunotherapy. Improved understanding of these processes and how they affect the immunogenomic architecture is the first step to developing more effective immunotherapies for CRC.

Lay Abstract: The immune system can play an important role in treating and controlling growth of colorectal cancer (CRC). New forms of cancer treatment, called immunotherapy, enable activation of the immune system to treat CRC. They can lead to very good responses in small numbers of patients. Not all patients respond to treatment and these treatments have a number of potentially serious side effects.

A number of tests have been devised to try and predict who would do well from treatment, such as the presence of microsatellite instability. However, this test is not very good and many patients with microsatellite instability will still do very poorly from treatment.

A new technique called immunogenomics now enables the accurate measurement of the immune system. I have previously found that activation of the immune system is dependent on the tumour cells. Tumour cells grow through the development of mutations and some cancer cells are better able to hide these mutations from the immune system.

In this project, I propose to gain a better understand of who could get immunotherapy and why some people do not respond to it. I will use immunogenomic techniques and assess how a cancer cell is able to hide mutations from the immune system. A better understanding of these mechanisms could enable the development of better treatments for CRCs.

Research Activity Codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health Categories: CANCER AND NEOPLASMS