Pharmacology and Chemical Biology Wan Lab High Impact Publications

Congratulations to Dr. Yong Wan and his team for two recent high impact journal publications in the Journal of Clinical Investigation:

"Pharmacological Suppression of the OTUD4-CD73 Proteolytic Axis Revives Antitumor Immunity against Immune-Cold Breast Cancers," published March 26, 2024.

"CD8⁺ T cells sustain antitumor response by mediating crosstalk between adenosine A2A receptor and glutathione/GPX4," published March 5, 2024.

Article Published March 26, 2024:

"Pharmacological Suppression of the OTUD4-CD73 Proteolytic Axis Revives Antitumor Immunity against Immune-Cold Breast Cancers".

TNBC is one of the most aggressive subtypes of breast cancer with limited treatment options. While PD-L1 inhibitors have brought hope to some patients with TNBC and have shown significant effects in initial treatments, the inherently immunosuppressive nature of the tumor microenvironment can effectively "cultivate" resistance in tumor cells to such therapies, consequently limiting the durability and universality of therapeutic effects.

A recent breakthrough was published online in "The Journal of Clinical Investigation" by a team led by Professor Yong Wan from the Department of Pharmacology and Chemical Biology, Emory University School of Medicine. Their paper, entitled "Pharmacological Suppression of the OTUD4-CD73 Proteolytic Axis Revives Antitumor Immunity against Immune-Suppressive Breast Cancers," unveiled the degradation and stability control mechanisms of the CD73 protein and introduced a new small molecule compound designed to inhibit the stability of the immune checkpoint protein CD73. This development is poised to enhance the effectiveness of immunotherapy for "immune-cold" TNBC.

Investigators have identified that the anomalously high expression of CD73 in TNBC correlates with post-translational modifications (PTMs) of proteins and that the upstream protein OTUD4 is a novel target for improving the anti-cancer immune response in TNBC. Through multi-omics analyses, researchers have not only elucidated the yin-yang regulatory mechanism of CD73 in tumors—governed by the ubiquitylation by TRIM21 and the deubiquitylation by OTUD4—but also elucidate the complex biological processes that influence the entire tumor microenvironment. This research offers new insights into CD73's role in tumor immune escape and specifies how TRIM21/OTUD4 interacts with CD73 and how this interaction is modulated. Moreover, it paves new pathways for drug development targeting CD73 and its regulatory mechanisms, providing strong guidance for personalized treatment. Importantly, the Wan and colleagues developed a new type of small molecule drug, ST80, targeting the interaction between OTUD4 and CD73, demonstrating its potential to reinvigorate CD8+ T cell activity and enhance tumor sensitivity to PD-L1 treatment, suggesting that precise drug interventions can directly transform the immune characteristics of the tumor milieu. Overall, this study emphasizes the significance of a comprehensive analysis and utilization of the complexity of the tumor microenvironment for disease management. This approach could enhance the efficacy of existing immunotherapy regimens and offer new hope to patients who have developed resistance to current treatments.

The study was supported and funded by the National Institutes of Health (NIH), the National Cancer Institute (NCI), and the Emory Winship Cancer Institute Breast Cancer Research Pilot Fund.

Article Published March 5, 2024:

"CD8⁺ T cells sustain antitumor response by mediating crosstalk between adenosine A2A receptor and glutathione/GPX4".

Antitumor responses of CD8⁺ T cells are tightly regulated by distinct metabolic fitness. High levels of glutathione (GSH) are observed in the majority of tumors, contributing to cancer progression and treatment resistance in part by preventing glutathione peroxidase 4–dependent (GPX4-dependent) ferroptosis. Here, the Wan Lab shows the necessity of adenosine A2A receptor (A2AR) signaling and the GSH/GPX4 axis in orchestrating metabolic fitness and survival of functionally competent CD8⁺ T cells. Activated CD8⁺ T cells treated ex vivo with simultaneous inhibition of A2AR and lipid peroxidation acquire a superior capacity to proliferate and persist in vivo, demonstrating a translatable means to prevent ferroptosis in adoptive cell therapy.

The Wan lab identifies a particular cluster of intratumoral CD8⁺ T cells expressing a putative gene signature of GSH metabolism (GMGS) in association with clinical response and survival across several human cancers. Their study addresses a key role of GSH/GPX4 and adenosinergic pathways in fine-tuning the metabolic fitness of antitumor CD8⁺ T cells.