Inhibition of MAN2A1 Enhances the Immune Response to Anti–PD-L1 in Human Tumors

Shi, Sailing; Gu, Shengqing Stan; Han, Tong; Zhang, Wubing; Huang, Lei; Li, Ziyi; Pan, Deng; Fu, Jingxin; Ge, Jun; Brown, Myles; Zhang, Peng; Jiang, Peng; Wucherpfennig, Kai W.; Liu, X. Shirley

doi:10.1158/1078-0432.ccr-20-0778

Cited by 39 publications

(34 citation statements)

References 83 publications

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“…A recent study found Man2a1-null cancer cells are more sensitive to T cellmediated tumor killing. This finding has translational relevance since pharmacological inhibition of MAN2A1 by swainsonine synergized with anti-PD-L1 in the treatment of melanoma and lung cancer (Shi et al, 2020). In the future, it would be interesting to explore whether circMAN2A1 participates in MAN2A1regulation, and in which manners circMAN2A1 involves in the regulation.…”

Section: Discussionmentioning

confidence: 87%

Revisiting the Relationship Between Alzheimer’s Disease and Cancer With a circRNA Perspective

Chen

Hao

2021

Front. Cell Dev. Biol.

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BackgroundIncreasing evidence indicates an association between the incidence of Alzheimer’s disease (AD) and cancer development. Despite advances being made by comparisons from epidemiological studies, common pathways and molecular mechanisms, little is known about the identities of the circular RNAs (circRNAs) involved in the development and progression of these two pathologies and their possible correlations. The aim of this study was to explore the circRNA relationship between AD and cancer.Materials and MethodsIn this investigation, circRNAs that were significantly dysregulated in AD or associated with AD diagnosis, clinical dementia severity, and neuropathological severity, were examined in a large panel of 28 cancer types. On the basis of shared abnormal circRNAs in AD and cancers, we constructed a circRNA-micro RNA (miRNA)-messenger RNA (mRNA) network by leveraging experimentally identified miRNA-circRNA and miRNA-mRNA interactions from crosslinking-immunoprecipitation sequencing data.ResultsAn inverse correlation of expression pattern was found in acute myeloid leukemia, juvenile myelomonocytic leukemia, renal cell carcinoma, and myelofibrosis. CircRNAs associated with AD diagnosis and clinical severity demonstrated negative correlation in more cancer types. Notably, differentially expressed candidate circRNAs in temporal lobe epilepsy were not associated with any cancers. Gene Ontology and KEGG pathway analysis suggested the circRNA-regulated genes are significantly associated with interleukin-12-mediated signaling and viral response. CircPICALM, circRTN4 and circMAN2A1 are the hub nodes in the circRNA-miRNA-target network.ConclusionOur results indicated the relevance of inflammation signaling as a common pathogenesis shared by cancer and AD and provided novel insight for therapeutics targeting circRNAs.

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Section: Discussionmentioning

confidence: 87%

Revisiting the Relationship Between Alzheimer’s Disease and Cancer With a circRNA Perspective

Chen

Hao

2021

Front. Cell Dev. Biol.

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“…It has been well documented that aberrant glycosylation contributes to tumorigenesis in multiple cancer types [18][19][20]. In addition, aberrant glycosylation increased cancer stem cell ability for tumour proliferation [21] and also could weakened immune checkpoint blockade against cancer cells [22,23]. Simultaneously, accumulating data showed that protein glycosylation and trafficking were regulated by the conserved oligomeric Golgi (COG) complex [24].…”

Section: Discussionmentioning

confidence: 99%

Abnormal Expression and Prognosis Value of COG Complex Members in Kidney Renal Clear Cell Carcinoma (KIRC)

2021

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Kidney renal clear cell carcinoma (KIRC) is the most aggressive subtype of kidney tumours with poor prognosis as well as the increasing incidence rate in worldwide. The conserved oligomeric Golgi (COG) complex is an eight-subunit (Cog1-8) peripheral Golgi protein that controls membrane trafficking and protein glycosylation and plays vital roles in human disease including cancers. Therefore, to uncover the prognostic value of COG complex in KIRC, a series of databases, including UALCAN database, GEPIA database, and Kaplan-Meier plotter, were used to analyse the mRNA expression of COG complex subunits and their prognostic values in patients with KIRC in this study. Compared with normal counterparts, mRNA expression of six COG complex subunits was significantly downregulated in KIRC tissue in UALCAN database, while COG4 mRNA expression was significantly upregulated in KIRC tissue. Moreover, the survival analysis indicated that all members of COG complex subunits were closely related with the prognosis of KIRC patients, while COG1 and COG4 were significantly associated with unfavourable overall survival (OS), the rest of COG complex subunits were importantly correlated with favourable OS. Simultaneously, higher mRNA expression of COG3, COG6, and COG8 exhibits better progression-free survival (PFS) and disease-free survival (DFS) in KIRC patients. These results identified that COG complex subunits, especially COG3, COG6, and COG8, are potential prognostic biomarkers of KIRC patients and may offer effective and new strategies for more accurately diagnosing the patients with KIRC in advance.

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“…Later on, Kim et al found that 2-DG, as a PD-L1 deglycosylation agent, synergizes with the epidermal growth factor receptor (EGFR) inhibitor, gefitinib, in syngeneic breast cancer models [ 13 ]. Shi and colleagues integrated previously published clinical studies, functional screens, and omics databases and identified alpha-mannosidase 2 (MAN2A) as a regulator of T-cell dysfunction by controlling N-glycan maturation of PD-L1 in the Golgi apparatus [ 117 ]. Swainsonine, a potent inhibitor of MAN2A1, synergized with PD-L1 blockade in syngeneic cancer models that responded poorly to monotherapy [ 117 ].…”

Section: N-glycosylation As a Target For Cancer Immunotherapymentioning

confidence: 99%

“…Shi and colleagues integrated previously published clinical studies, functional screens, and omics databases and identified alpha-mannosidase 2 (MAN2A) as a regulator of T-cell dysfunction by controlling N-glycan maturation of PD-L1 in the Golgi apparatus [ 117 ]. Swainsonine, a potent inhibitor of MAN2A1, synergized with PD-L1 blockade in syngeneic cancer models that responded poorly to monotherapy [ 117 ]. As described above, B7-H4 depends on N-linked carbohydrates on the extracellular domain to resist proteolysis [ 90 ].…”

Section: N-glycosylation As a Target For Cancer Immunotherapymentioning

confidence: 99%

Glycosylation of Immune Receptors in Cancer

Sun

Kim

Lim

2021

Cells

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Evading host immune surveillance is one of the hallmarks of cancer. Immune checkpoint therapy, which aims to eliminate cancer progression by reprogramming the antitumor immune response, currently occupies a solid position in the rapidly expanding arsenal of cancer therapy. As most immune checkpoints are membrane glycoproteins, mounting attention is drawn to asking how protein glycosylation affects immune function. The answers to this fundamental question will stimulate the rational development of future cancer diagnostics and therapeutic strategies.

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Inhibition of MAN2A1 Enhances the Immune Response to Anti–PD-L1 in Human Tumors

Cited by 39 publications

References 83 publications

Revisiting the Relationship Between Alzheimer’s Disease and Cancer With a circRNA Perspective

Revisiting the Relationship Between Alzheimer’s Disease and Cancer With a circRNA Perspective

Abnormal Expression and Prognosis Value of COG Complex Members in Kidney Renal Clear Cell Carcinoma (KIRC)

Glycosylation of Immune Receptors in Cancer

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