Role of TCR signalling in the genesis of ALCL

Anaplastic large cell lymphoma (ALCL) is a cancer of the T cells of the immune system that belongs to a group of cancers called non-Hodgkin lymphomas (NHL). Unlike other T cell lymphomas, ALCL very rarely express a T cell receptor (TCR), a protein that helps the immune system to detect invading pathogens, on the surface of the tumour cells. The reasons for this and whether this is an important component of the lymphomagenic process remains unknown. We have shown that at least half of ALCL cases have the capacity to express a functional TCR; the other half have unusual T cell receptor rearrangements that would not normally be permissive of T cell development. These data suggest that for at least half of the patients, something has happened during T cell development that allows these abnormal cells to survive. Regardless, whatever the status of the TCR, it is rarely present on the cell surface raising the question of whether the TCR is actively downregulated as it is detrimental to tumour growth, or the tumour cells dont express it on their surface because it is not needed for their survival? If we can work out the answer to this question, we will be able to learn more about why and how this cancer occurs, specifically as it is more often seen in children particularly when a protein called anaplastic lymphoma kinase (ALK) is aberrantly expressed. In particular, if the former is correct, this might tell us that chronic stimulation of the TCR by, for example, inflammation might drive cancer development. Our previous data show that binding of the TCR to a strong antigen in the presence of aberrantly expressed ALK prevents cell proliferation, but if the antigen binds weakly in the presence of ALK, cells continue to divide leading to tumour growth. This suggests that the strength of binding of an antigenic protein to the TCR is important for chronic stimulation and development of cancer cells. We hypothesise that a high level of chronic antigenic exposure of incipient tumour cells is not compatible with tumour growth leading to selective downregulation of the TCR permitting aberrant ALK-induced transformation. Alternatively/additively, a chronic inflammatory microenvironment in which cytokines are present, drives sustained tumour growth. Specifically, as the tumour cells resemble a specialised type of T cell called a Th17 cell, but without a TCR and therefore resembling an innate lymphoid cell (ILC). Another mechanism that may contribute to tumour development is through the aryl hydrocarbon receptor (AHR), normally expressed by Th17 cells (and ALCL cells) which, when activated by a ligand, activates the enzyme CYP1A1, which can convert aryl hydrocarbons into cancer-inducing chemicals called epoxides. Epoxides directly induce DNA damage that we hypothesise also contributes to tumorigenesis. Therefore, this study aims to dissect the role of a chronically stimulated TCR, an inflammatory microenvironment and epoxide-induced DNA damage in the development of ALCL. Not only will this tell us more about how and why this cancer develops but may also inform us of novel therapeutic targets.