<i>In vivo</i> anti‐V‐ATPase antibody treatment delays ovarian tumor growth by increasing antitumor immune responses

Kulshrestha, Arpita; Katara, Gajendra K.; Ibrahim, Safaa A.; Riehl, Valerie; Schneiderman, Sylvia; Bilal, Mahmood Y.; Young, Alexandria N.; Levine, Shayna; Fleetwood, Sara; Dolan, James; Gilman‐Sachs, Alice; Beaman, Kenneth D.

doi:10.1002/1878-0261.12782

Cited by 13 publications

(15 citation statements)

References 57 publications

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“…The blue scale color map represents the number of publications where a specific isoform overexpression was reported. This heatmap was built based on the following publications 50,83,85,87,89,91,93,96,99–101,103–123 . CNS, central nervous system; mRNA, messenger RNA [Color figure can be viewed at wileyonlinelibrary.com]…”

Section: V‐atpases: Attractive Targets For a Multitude Of Human Diseasesmentioning

confidence: 99%

Emerging insights on the role of V‐ATPase in human diseases: Therapeutic challenges and opportunities

Santos-Pereira

Rodrigues

Côrte‐Real

2021

Medicinal Research Reviews

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The control of the intracellular pH is vital for the survival of all organisms. Membrane transporters, both at the plasma and intracellular membranes, are key players in maintaining a finely tuned pH balance between intra‐ and extracellular spaces, and therefore in cellular homeostasis. V‐ATPase is a housekeeping ATP‐driven proton pump highly conserved among prokaryotes and eukaryotes. This proton pump, which exhibits a complex multisubunit structure based on cell type‐specific isoforms, is essential for pH regulation and for a multitude of ubiquitous and specialized functions. Thus, it is not surprising that V‐ATPase aberrant overexpression, mislocalization, and mutations in V‐ATPase subunit‐encoding genes have been associated with several human diseases. However, the ubiquitous expression of this transporter and the high toxicity driven by its off‐target inhibition, renders V‐ATPase‐directed therapies very challenging and increases the need for selective strategies. Here we review emerging evidence linking V‐ATPase and both inherited and acquired human diseases, explore the therapeutic challenges and opportunities envisaged from recent data, and advance future research avenues. We highlight the importance of V‐ATPases with unique subunit isoform molecular signatures and disease‐associated isoforms to design selective V‐ATPase‐directed therapies. We also discuss the rational design of drug development pipelines and cutting‐edge methodological approaches toward V‐ATPase‐centered drug discovery. Diseases like cancer, osteoporosis, and even fungal infections can benefit from V‐ATPase‐directed therapies.

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Section: V‐atpases: Attractive Targets For a Multitude Of Human Diseasesmentioning

confidence: 99%

Emerging insights on the role of V‐ATPase in human diseases: Therapeutic challenges and opportunities

Santos-Pereira

Rodrigues

Côrte‐Real

2021

Medicinal Research Reviews

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“…This approach is facilitated by the fact that the extracellular domains have been clearly defined both through biochemistry [141] and through structural analysis using cryo-electron microscopy [62]. A recent report showed that monoclonal antibodies against the V-ATPase a2 subunit delayed ovarian tumor growth [142]. The inhibitory antibody was generated against amino acids 488-510 in human a2, which the authors stated is in the "transmembrane region of the protein" [143].…”

Section: The Potential Of A3 As a Therapeutic Target For Osteolytic Diseasesmentioning

confidence: 99%

The V-ATPase a3 Subunit: Structure, Function and Therapeutic Potential of an Essential Biomolecule in Osteoclastic Bone Resorption

Chu

Zirngibl

Manolson

2021

IJMS

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This review focuses on one of the 16 proteins composing the V-ATPase complex responsible for resorbing bone: the a3 subunit. The rationale for focusing on this biomolecule is that mutations in this one protein account for over 50% of osteopetrosis cases, highlighting its critical role in bone physiology. Despite its essential role in bone remodeling and its involvement in bone diseases, little is known about the way in which this subunit is targeted and regulated within osteoclasts. To this end, this review is broadened to include the three other mammalian paralogues (a1, a2 and a4) and the two yeast orthologs (Vph1p and Stv1p). By examining the literature on all of the paralogues/orthologs of the V-ATPase a subunit, we hope to provide insight into the molecular mechanisms and future research directions specific to a3. This review starts with an overview on bone, highlighting the role of V-ATPases in osteoclastic bone resorption. We then cover V-ATPases in other location/functions, highlighting the roles which the four mammalian a subunit paralogues might play in differential targeting and/or regulation. We review the ways in which the energy of ATP hydrolysis is converted into proton translocation, and go in depth into the diverse role of the a subunit, not only in proton translocation but also in lipid binding, cell signaling and human diseases. Finally, the therapeutic implication of targeting a3 specifically for bone diseases and cancer is discussed, with concluding remarks on future directions.

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“… 38 39 These molecules play significant roles in mediating an immune suppressive microenvironment in the tumor and ATPases are identified as promising targets for immunotherapy and combination therapy to combat tumors. 40 41 Kulshrestha et al showed that V-ATPase inhibition using a monoclonal antibody enhances the antitumor immune response, drastically inhibiting ovarian tumor growth without evident side effects. 40 Our previous study demonstrated that MET interacts with V-ATPase and suppresses liver cancer immunogenicity through the activation of the mammalian target of rapamycin.…”

Section: Discussionmentioning

confidence: 99%

“… 40 41 Kulshrestha et al showed that V-ATPase inhibition using a monoclonal antibody enhances the antitumor immune response, drastically inhibiting ovarian tumor growth without evident side effects. 40 Our previous study demonstrated that MET interacts with V-ATPase and suppresses liver cancer immunogenicity through the activation of the mammalian target of rapamycin. 41 Moreover, the V-ATPase inhibitor Con A significantly enhances the efficacy of chemotherapy-based vaccination in a mouse model.…”

Section: Discussionmentioning

confidence: 99%

Oncolytic peptide LTX-315 induces anti-pancreatic cancer immunity by targeting the ATP11B-PD-L1 axis

Tang

Huang

Zhang

et al. 2022

J Immunother Cancer

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BackgroundLTX-315 is an oncolytic peptide deriving from bovine lactoferrin, with the ability to induce cancer immunogenic cell death. However, the mechanism used by LTX-315 to trigger the antitumor immune response is still poorly understood. The expression of programmed cell death ligand 1 (PD-L1) largely determines the efficacy and effectiveness of cancer immunotherapies targeting this specific immune checkpoint. This study aimed to demonstrate the potential effect and mechanism of LTX-315 in PD-L1 inhibition-induced anti-pancreatic cancer immunity.MethodsBoth immunodeficient and immunocompetent mouse models were used to evaluate the therapeutic efficacy of monotherapy and combination therapy. Flow cytometry and immunohistochemistry were used to assess the immune microenvironment. Multiomic analysis was used to identify the potential target and down-streaming signaling pathway. Both in-house tissue microarray and open accessed The Cancer Genome Atlas data sets were used to evaluate the clinical relevance in pancreatic cancer prognosis.ResultsLTX-315 treatment inhibited PD-L1 expression and enhanced lymphocyte infiltration in pancreatic tumors. ATP11B was identified as a potential target of LTX-315 and a critical regulator in maintaining PD-L1 expression in pancreatic cancer cells. As regards the mechanism, ATP11B interacted with PD-L1 in a CKLF-like MARVEL transmembrane domain containing 6 (CMTM6)-dependent manner. The depletion of ATP11B promoted CMTM6-mediated lysosomal degradation of PD-L1, thus reactivating the immune microenvironment and inducing an antitumor immune response. The significant correlation among ATP11B, CMTM6, and PD-L1 was confirmed in clinical samples of pancreatic cancer.ConclusionsLTX-315 was first identified as a peptide drug inducing PD-L1 downregulation via ATP11B. Therefore, LTX-315, or the development of ATP11B-targeting drugs, might improve the efficacy of cancer immunotherapy.

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In vivo anti‐V‐ATPase antibody treatment delays ovarian tumor growth by increasing antitumor immune responses

Cited by 13 publications

References 57 publications

Emerging insights on the role of V‐ATPase in human diseases: Therapeutic challenges and opportunities

Emerging insights on the role of V‐ATPase in human diseases: Therapeutic challenges and opportunities

The V-ATPase a3 Subunit: Structure, Function and Therapeutic Potential of an Essential Biomolecule in Osteoclastic Bone Resorption

Oncolytic peptide LTX-315 induces anti-pancreatic cancer immunity by targeting the ATP11B-PD-L1 axis

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