WORLD CLASS BASIC, TRANSLATIONAL AND CLINICAL RESEARCH

Overview

Our multidisciplinary group studies cancer biology, from the basic causes of cancer to how patients respond to treatment. Over the past year, we described how patient blood can be used to monitor which patients will respond to immunotherapy, studies that have improved our understanding of the human immune system and provided new methods to identify which patients are likely to respond to therapy and which patients are unlikely to respond. We also identified new prognostic markers and new therapeutic targets in prostate cancer. Together, these studies provide new possible ways of monitoring cancer so that their treatment can be tailored for individual patients.

Immunotherapy

Immunotherapy has been transforming the melanoma treatment paradigm over the past decade, affording sustained survival benefit in some patients. However, we do not yet fully understand the mechanisms that determine response to immunotherapy and most patients with malignant melanoma still die of their disease. Our group has previously shown that in patients who respond to immunotherapy a small subset of circulating T cells that we have called immune effector T cells (TIE) expand within 3 weeks of starting treatment. In the same study, we showed that changes in clonality (expansion of one or a small number of predominant T cell clones) or diversity (expansion of many T cell clones) of circulating T cells in response to immunotherapy also provided an indication of whether a patient would go on to respond to immunotherapy.

Response of immune system to cancer and immunotherapy

In the past year, we continued to study the immune system’s response to cancer and immunotherapy. In one study, we sought to understand whether the extent of the TIE expansion we previously described in patients that responded to immunotherapy correlated in some way with observed tumour shrinkage. Comparing tumour measurements at the start of therapy and 12 weeks after therapy, we confirmed an inverse relationship between tumour size and TIE cell expansion, further validating TIE cell expansion as a biomarker for immunotherapy response. We examined if the expansion of TIE cells and the changes in T cell clonality and diversity were influenced by clinical variables such as sex, disease stage, BRAF mutation status, LDH levels or age. We found that whilst TIE cell expansion was not influenced by the first four clinical parameters, changes in the clonality and diversity of T cells in response to immunotherapy were influenced by age. Specifically, we observed that in patients younger than 70 years of age, T cells exhibited a trend towards increased diversity in response to immunotherapy, whereas in patients of 70 years and over, we observed a trend towards increased clonality. The increased diversity in younger patients but increased clonality in older patients is consistent with the reduction in thymus function as we age (thymus involution) and is important because it suggests that biological variation driven by age should be taken into account when developing immunotherapy approaches, new treatments or diagnostic tools.

Tumour T cells

In a separate study, we focused on the different types of T cells that reside within tumours, examining their clonality and diversity. We discovered that the diversity of T cell receptors in the tumour resident T cells is prognostic for survival not only in melanoma, but also in breast cancer, certain lung cancers, renal and testicular cancers, and thymoma, irrespective of whether patients received immunotherapy or not. This provides interesting new insight into the interactions between the immune system and tumour cells. Additionally, we discovered that the clonality of tumour resident T cells is predictive for response and survival after anti-PD1 based immunotherapy (Figure 1), providing a potential biomarker that can identify patients that are most likely to respond to these immunotherapies. There is a great need to identify markers of response to these therapies so they can be administered to the patients that will derive benefit from them, whilst sparing other patients the potential side effects of these therapies and affording them more time to explore other treatment options.

Basic biology of cancer

Alongside these translational studies focused on identifying markers of response to therapy, we also continue our studies of the basic biology of cancer, seeking out vulnerabilities that may be exploited therapeutically. One such study of prostate cancer (PCa), the fifth leading cause of cancer deaths worldwide, revealed a 7-microRNA (miR) signature that identifies PCa primary tumours that are more prone to metastasise, providing a mechanism to help clinicians to stratify patients more accurately for follow up and therapy (Figure 2a, b). MiRs are small RNA molecules that regulate many biological processes, and analysis of our signature has provided clues to novel therapeutic options because we discovered that one of the miRs in our signature, miR-378a, impairs the metabolism of glucose by PCa cells. This is because miR-378a blocks the expression of a protein called GLUT1 (glucose transporter 1) in PCa cells, reducing their ability to use glucose to support their proliferation (division) (Figure 2c, d). These studies reveal that metabolism could be an exciting therapeutic target in aggressive prostate cancer.

Early detection

In addition to understanding and developing therapeutic options for advanced cancer, we continue to seek ways in which cancer can be prevented or detected at earlier stages. Especially in the context of rare cancer types, such as melanoma of the eye, identifying their underlying drivers can be a key factor in preventing their development. Our studies of conjunctival melanoma, set in the context of a series of recent studies focused on the genetic changes that drive ocular melanomas, suggest that whilst different genetic events drive melanoma at specific sites (the skin, the eye, mucosal membranes), ultraviolet radiation (UVR) imposes additional events over these specific processes to accelerate melanoma development. It is generally accepted that this is particularly important for the skin, but our data show it is very important to remember that is can also happen in the eyes (particularly the conjunctiva and iris) and mucosal membranes that are sun-exposed, such as the lips. Our findings emphasise the importance of promoting UVR protection with sunblock for the skin, UVR protective lip balm for the lips and sunglasses for the eyes. The data also suggest that therapies currently approved for skin melanoma should also be considered for melanomas at other sites, guided by their underlying genetics.