Proteolysis-targeting chimera against BCL-XL destroys tumor-infiltrating regulatory T cells

Abstract

Regulatory T cells (Tregs) play an important role in maintaining immune homeostasis and, within tumors, their upregulation is common and promotes an immunosuppressive microenvironment. Therapeutic strategies that can eliminate Tregs in the tumor (i.e., therapies that do not run the risk of affecting normal tissues), are urgently needed for the development of cancer immunotherapies. Here we report our discovery of B-cell lymphoma extra-large (BCL-XL) as a potential molecular target of tumor-infiltrating (TI) Tregs. We show that pharmacological degradation of BCL-XL using a newly developed platelet-sparing BCL-XL Proteolysis-targeting chimera (PROTAC) induces the apoptosis of TI-Tregs and the activation of TI-CD8+ T cells. Moreover, these activities result in an effective suppression of syngeneic tumor growth in immunocompetent, but not in immunodeficient or CD8+ T cell-depleted mice. Notably, treatment with BCL-XL PROTAC does not cause detectable damage within several normal tissues or thrombocytopenia. These findings identify BCL-XL as a target in the elimination of TI-Tregs as a component of cancer immunotherapies, and that the BCL-XL-specific PROTAC has the potential to be developed as a therapeutic for cancer immunotherapy.

Therapeutics Targeting the Core Apoptotic Machinery

“…DT2216 has demonstrated preclinical activity against BCL-X L -dependent T cell lymphomas without causing significant platelet toxicity specifically degrading BCL-X L while sparing BCL-2 [ 47 , 49 ]. An additional similar PROTAC, PZ15227, has also recently emerged which induces BCL-X L polyubiquitination and degradation [ 50 ]. BCL-X L has been reported to be highly expressed in the tumor-infiltrating regulatory T-cells (Treg) population in several cancers.…”

“…BCL-X L has been reported to be highly expressed in the tumor-infiltrating regulatory T-cells (Treg) population in several cancers. Both PROTAC compounds have demonstrated induction of apoptosis in Tregs and the activation of tumor infiltrating CD8+ T cells resulting in a decrease in tumor growth in immunocompetent tumor models; this suggests that targeting of BCL-X L may also have the potential to improve cancer immunotherapy [ 50 ]. UBX1325 (Unity Biotechnology, San Franscisco, CA, USA), another specific BCL- X L inhibitor, is also being evaluated in patients with diabetic macular edema widening the scope of this class of agents beyond cancer (NCT04537884, NCT04857996).…”

Overcoming Gemcitabine Resistance in Pancreatic Cancer Using the BCL-XL–Specific Degrader DT2216

“…Since on-target thrombocytopenia is a major hurdle in the clinical development of BCL-X L inhibitors, we recently adopted a novel PROTAC technology to overcome this toxicity by converting ABT263 (BCL-X L /2 dual inhibitor) into a BCL-X L selective PROTAC, named DT2216 (20)(21)(22). DT2216 is currently in phase I clinical studies for patients with relapsed/refractory malignancies (NCT04886622).…”

“…Recently, using emerging Proteolysis Targeting Chimera (PROTAC) technology, we successfully converted ABT263 (a BCL-X L /2 inhibitor) into DT2216, a plateletsparing BCL-X L -selective PROTAC that targets BCL-X L to the Von Hippel-Lindau (VHL) E3 ligase for ubiquitination and proteasomal degradation (20). DT2216 has shown promising antitumor activities in BCL-X L -dependent hematologic malignancies when used as single agent therapy and in multiple solid tumors when combined with conventional chemotherapy (20)(21)(22).…”

The Biological Function, Mechanism, and Clinical Significance of m6A RNA Modifications in Head and Neck Carcinoma: A Systematic Review

“…Several studies have demonstrated that tumor immune cells can perform vastly different or even opposite functions under the influence of the tumor microenvironment ( Jiménez-Sánchez et al, 2017 ; Wagner et al, 2019 ; Luoma et al, 2020 ; Kolb et al, 2021 ), with some studies suggesting that m6A modification plays an important regulatory role in these immune cells. Here, we discuss the relationship between immune cell infiltration and m6A modification in HNSCC, with a view to providing directions for future studies.…”