CD8+ T cells, a crucial part of the immune system that grants immunity against cancer, have been the focal point of cancer-fighting treatments. Recent research has unveiled two primary subgroups of these cells within tumors: stem-like cells lacking anti-tumor capabilities, and terminally differentiated CD8+ T cells, arising from the stem-like cells, which possess cytotoxic abilities against tumor cells. Tumor-draining lymph nodes (TDLNs) have been identified as the primary location for these cells. However, the molecular mechanisms governing the transformation of stem-like cells into terminally differentiated CD8+ T cells remain elusive.
Moreover, recent scientific investigations conducted on mice have provided insights into the involvement of CD69, a transmembrane functional glycoprotein commonly found on CD8+ T cells in both the tumor microenvironment and tumor-draining lymph nodes (TDLNs), in anti-tumor immune responses. However, the comprehensive molecular mechanism underlying its role remains incompletely understood. Consequently, in order to delve into the molecular function of CD69 in anti-tumor immune reactions, a group of researchers from Chiba University's Graduate School of Medicine in Japan conducted a study. The findings of their research were published on May 22, 2023, in the journal Cancer Immunology Research, which is associated with the American Association for Cancer Research. Senior Lecturer Ryo Koyama-Nasu served as the first author of this study, and the team included Dr. Motoko Y. Kimura and Dr. Toshinori Nakayama from Chiba University.
In order to assess the significance of targeting CD69 to enhance anti-tumor responses, the researchers employed various strains of mice as tumor models in their investigation. This included mice lacking the expression of the CD69 molecule, known as CD69-deficient mice. Additionally, they examined the response of mice following the administration of an anti-CD69 antibody, an immune molecule designed to selectively bind to CD69 and impede its function.
Utilizing single-cell transcriptomics, the researchers made a significant discovery that CD69 plays a crucial role in regulating the differentiation process of CD8+ T cells within tumor-draining lymph nodes (TDLNs). They also observed that the absence of CD69 led to a decrease in the expression of a transcription factor called TOX. Notably, TOX is responsible for modulating anti-tumor activity at the RNA regulation level. Dr. Koyama-Nasu elaborated on this finding, stating that "The deficiency of CD69 resulted in reduced TOX expression in tumor-specific CD8+ T cells within TDLNs, thereby facilitating the differentiation of stem-like CD8+ T cells into fully functional terminally differentiated CD8+ T cells within TDLNs."
This discovery is of great significance as it elucidates the mechanism by which CD69 governs the development of tumor-specific CD8+ T cells within tumor-draining lymph nodes (TDLNs). Additionally, the researchers observed that mice lacking CD69 exhibited an elevated generation of fully matured CD8+ T cells within the tumor microenvironment. This increase in terminally differentiated CD8+ T cells resulted in heightened anti-tumor activity, indicating the important role of CD69 in regulating the anti-tumor immune response.
Regarding this matter, Dr. Kimura, the corresponding author of the study, provides further insights. They state, "We observed that the combination of anti-CD69 treatment with the immune checkpoint inhibitor anti-PD-1 enhances its effectiveness by augmenting the pool of available stem-like CD8+ T cells. This combination therapy proves to be efficacious, even in cases of immunorefractory melanoma." Furthermore, it is worth noting that CD69 deficiency or anti-CD69 treatment did not have any detrimental effects on the overall health of the mice. This suggests that the absence of CD69 does not negatively impact cellular functioning, thereby supporting the potential safety of targeting CD69 for therapeutic purposes.
In conclusion, the researchers propose that the abundant presence of CD69 on the surface of CD8+ T cells within tumor-draining lymph nodes (TDLNs) in human cancers highlights its potential as a novel therapeutic target for immunotherapies. They suggest that conducting clinical evaluations using humanized monoclonal antibodies that specifically recognize human CD69 could offer a promising and innovative strategy for future cancer immunotherapies. By targeting CD69, it may be possible to enhance anti-tumor immune responses and improve the efficacy of immunotherapeutic approaches in treating cancer.
(DVR/Newswise)