Loss of Diacylglycerol Kinase α Enhances Macrophage Responsiveness

Manigat, Laryssa; Granade, Mitchell E.; Taori, Suchet; Miller, Charlotte A.; Vass, Luke R.; Zhong, Xiao‐Ping; Harris, Thurl E.; Purow, Benjamin

doi:10.3389/fimmu.2021.722469

Cited by 3 publications

(3 citation statements)

References 42 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In indications including hepatocellular carcinoma, osteosarcoma, melanoma, and glioblastoma, either DGKα or DGKζ was found to promote tumor cell growth (35,(38)(39)(40)(41). DGK regulation of DAG signaling has also been implicated in regulating other immune populations, such as natural killer cells, macrophages, and dendritic cells (42)(43)(44), as well as fibroblasts in response to irradiation (40). Therefore, we anticipate that DGKα/ζ inhibitors could have a broader impact within the tumor microenvironment, which needs to be addressed in future studies.…”

Section: Discussionmentioning

confidence: 99%

DGKα/ζ inhibitors combine with PD-1 checkpoint therapy to promote T cell–mediated antitumor immunity

Wichroski,

Benci,

Liu

et al. 2023

Sci. Transl. Med.

View full text Add to dashboard Cite

Programmed cell death protein 1 (PD-1) immune checkpoint blockade therapy has revolutionized cancer treatment. Although PD-1 blockade is effective in a subset of patients with cancer, many fail to respond because of either primary or acquired resistance. Thus, next-generation strategies are needed to expand the depth and breadth of clinical responses. Toward this end, we designed a human primary T cell phenotypic high-throughput screening strategy to identify small molecules with distinct and complementary mechanisms of action to PD-1 checkpoint blockade. Through these efforts, we selected and optimized a chemical series that showed robust potentiation of T cell activation and combinatorial activity with αPD-1 blockade. Target identification was facilitated by chemical proteomic profiling with a lipid-based photoaffinity probe, which displayed enhanced binding to diacylglycerol kinase α (DGKα) in the presence of the active compound, a phenomenon that correlated with the translocation of DGKα to the plasma membrane. We further found that optimized leads within this chemical series were potent and selective inhibitors of both DGKα and DGKζ, lipid kinases that constitute an intracellular T cell checkpoint that blunts T cell signaling through diacylglycerol metabolism. We show that dual DGKα/ζ inhibition amplified suboptimal T cell receptor signaling mediated by low-affinity antigen presentation and low major histocompatibility complex class I expression on tumor cells, both hallmarks of resistance to PD-1 blockade. In addition, DGKα/ζ inhibitors combined with αPD-1 therapy to elicit robust tumor regression in syngeneic mouse tumor models. Together, these findings support targeting DGKα/ζ as a next-generation T cell immune checkpoint strategy.

show abstract

Section: Discussionmentioning

confidence: 99%

DGKα/ζ inhibitors combine with PD-1 checkpoint therapy to promote T cell–mediated antitumor immunity

Wichroski,

Benci,

Liu

et al. 2023

Sci. Transl. Med.

View full text Add to dashboard Cite

show abstract

“…A new report from our group indicates that DGKα also acts to regulate macrophages; DGKα knockout/knockdown increases macrophage responsiveness to diverse stimuli [ 55 ]. This may indicate that DGKα inhibition could turn macrophages and microglia from a pro-GBM phenotype toward an anti-GBM phenotype, but this remains to be demonstrated.…”

Section: Indirect Activities Of Dgkα Inhibition On Gbm—potential Immu...mentioning

confidence: 99%

Delivering Glioblastoma a Kick—DGKα Inhibition as a Promising Therapeutic Strategy for GBM

Purow

2022

Cancers

View full text Add to dashboard Cite

Diacylglycerol kinase α (DGKα) inhibition may be particularly relevant for the treatment of glioblastoma (GBM), a relatively common brain malignancy incurable with current therapies. Prior reports have shown that DGKα inhibition has multiple direct activities against GBM cells, including suppressing the oncogenic pathways mTOR and HIF-1α. It also inhibits pathways associated with the normally treatment-resistant mesenchymal phenotype, yielding preferential activity against mesenchymal GBM; this suggests possible utility in combining DGKα inhibition with radiation and other therapies for which the mesenchymal phenotype promotes resistance. The potential for DGKα inhibition to block or reverse T cell anergy also suggests the potential of DGKα inhibition to boost immunotherapy against GBM, which is generally considered an immunologically “cold” tumor. A recent report indicates that DGKα deficiency increases responsiveness of macrophages, indicating that DGKα inhibition could also have the potential to boost macrophage and microglia activity against GBM—which could be a particularly promising approach given the heavy infiltration of these cells in GBM. DGKα inhibition may therefore offer a promising multi-pronged attack on GBM, with multiple direct anti-GBM activities and also the ability to boost both adaptive and innate immune responses against GBM. However, both the direct and indirect benefits of DGKα inhibition for GBM will likely require combinations with other therapies to achieve meaningful efficacy. Furthermore, GBM offers other challenges for the application of DGKα inhibitors, including decreased accessibility from the blood-brain barrier (BBB). The ideal DGKα inhibitor for GBM will combine potency, specificity, and BBB penetrability. No existing inhibitor is known to meet all these criteria, but the strong potential of DGKα inhibition against this lethal brain cancer should help drive development and testing of agents to bring this promising strategy to the clinic for patients with GBM.

show abstract

“…Lipid metabolic homeostasis, for example, is crucial for macrophage function in general (not just within the high-grade glioma tumor microenvironment). Triacylglycerol synthesis in lipid droplet development is necessary for macrophage activation and inflammatory cytokine release in murine models (20). However, diacylglyerol Kinase α (DGKα) is involved in lipid metabolism and T cell checkpoint to support anergy.…”

Section: Myeloid Cell Metabolismmentioning

confidence: 99%

Immunometabolism, a new therapeutic development for immunotherapies of high-grade gliomas: a narrative review

Wu¹,

Ren²,

Lim³

2022

Chin Clin Oncol

View full text Add to dashboard Cite

Background and Objective: Immunotherapy has yielded significant improvements in survival for many cancer types, but its impact on glioblastoma (GBM) has been relatively muted. There is a growing interest in understanding the role of cancer metabolism and its role in tumor growth and therapeutic response. Thus, it is equally important to consider the clinical implications of immune cell metabolism on cancer progression and implications for therapeutic development. Our objective is to present new developments in immunometabolic research that are relevant to immunotherapy development for high-grade gliomas.Methods: A literature search and review was conducted, regarding original research articles studying metabolic pathways of immune cells in high-grade gliomas. Searches were conducted in PubMed and Embase databases on May 15 and June 13, 2022. English-language original research articles were selected and prioritized based on their inclusion of findings related to metabolic changes in myeloid and lymphoid cells in the glioma tumor microenvironment.

show abstract

Loss of Diacylglycerol Kinase α Enhances Macrophage Responsiveness

Cited by 3 publications

References 42 publications

DGKα/ζ inhibitors combine with PD-1 checkpoint therapy to promote T cell–mediated antitumor immunity

DGKα/ζ inhibitors combine with PD-1 checkpoint therapy to promote T cell–mediated antitumor immunity

Delivering Glioblastoma a Kick—DGKα Inhibition as a Promising Therapeutic Strategy for GBM

Immunometabolism, a new therapeutic development for immunotherapies of high-grade gliomas: a narrative review

Contact Info

Product

Resources

About