<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 12 publications

(13 citation statements)

References 57 publications

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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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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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“… 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 addition, proton pump inhibitors can reverse H (+) ion homeostasis in the tumor microenvironment and induce tumor cell death (139). Some in vivo and in vitro experiments have shown proton pump inhibitors enhance the anti-tumor effect of TAM, but their exact role in BC needs to be further studied (139)(140)(141). Therefore, reducing the occurrence of resistance in BC by focusing on the alteration of the biophysical tumor microenvironment to regulate the polarization of TAMs may also be a promising therapeutic strategy in the future.…”

Section: Discussionmentioning

confidence: 99%

Tumor-Associated Macrophages: Critical Players in Drug Resistance of Breast Cancer

Xiao

Yin

et al. 2021

Front. Immunol.

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Drug resistance is one of the most critical challenges in breast cancer (BC) treatment. The occurrence and development of drug resistance are closely related to the tumor immune microenvironment (TIME). Tumor-associated macrophages (TAMs), the most important immune cells in TIME, are essential for drug resistance in BC treatment. In this article, we summarize the effects of TAMs on the resistance of various drugs in endocrine therapy, chemotherapy, targeted therapy, and immunotherapy, and their underlying mechanisms. Based on the current overview of the key role of TAMs in drug resistance, we discuss the potential possibility for targeting TAMs to reduce drug resistance in BC treatment, By inhibiting the recruitment of TAMs, depleting the number of TAMs, regulating the polarization of TAMs and enhancing the phagocytosis of TAMs. Evidences in our review support it is important to develop novel therapeutic strategies to target TAMs in BC to overcome the treatment of resistance.

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

Cited by 12 publications

References 57 publications

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

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

Tumor-Associated Macrophages: Critical Players in Drug Resistance of Breast Cancer

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