Scientists from Japan have identified regulator CD69, which controls the differentiation of CD8+ T cells within tumour-draining lymph nodes, thereby regulating anti-tumour immunity.
Future cancer treatment based on antibodies against CD69 could enhance anti-tumour immune responses of CD8+ T cells and lead to more efficient cancer therapies.
CD8+ T cells have been the focal point of anti-cancer therapies. Recent studies have identified two major subpopulations of these cells present within the tumour – the stem-like cells that do not have anti-tumour activity, and the terminally differentiated CD8+ T cells, which are generated from the stem-like cells and have cytotoxic function on tumour cells.
Tumour-draining lymph nodes (TDLNs) have been found to be the primary site for the presence of these cells. However, the molecular mechanisms responsible for the generation of stem-like cells into terminally differentiated CD8+ T cells are yet to be understood.
Further, scientific studies on mice have given a glimpse into the involvement of CD69, a transmembrane functional glycoprotein often expressed on CD8+ T cells in the tumour microenvironment and the TDLNs, in anti-tumour immunity.
Promising future for immunotherapy
Using single-cell transcriptomics, the scientists found that CD69 is a critical component that regulates the differentiation of CD8+ T cells present within TDLNs. They further observed that the deficiency of CD69 results in a reduced expression of a transcription factor, TOX – a molecule that reduces anti-tumour activity at the level of RNA regulation.
Dr Koyama-Nasu, first author and Senior Lecturer at the Graduate School of Medicine at Chiba University, Japan, explained: “CD69 deficiency resulted in reduced expression of the transcription factor TOX in tumour-specific CD8+ T cells in TDLNs, promoting differentiation of stem-like CD8+ T cells into the functional terminally differentiated CD8+ T cells in TDLNs.”
The team further noted that CD69-deficient mice showed increased production of terminally differentiated CD8+ T cells in the tumour microenvironment, which led to enhanced anti-tumour activity.
Moreover, CD69 deficiency or anti-CD69 treatment did not have any negative impact on the health of mice, indicating that the absence of CD69 would not negatively affect cellular functioning.
The scientists conclude that the frequent expression of CD69 on the surface of CD8+ T cells in TDLNs in human cancers makes it a novel therapeutic target for immunotherapies. Potential clinical evaluations of humanised monoclonal antibodies that recognise human CD69 could provide a new and promising strategy for future cancer immunotherapies.