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

Autor: Valerie Riehl, Sylvia Schneiderman, Shayna Levine, Alexandria N. Young, Safaa A. Ibrahim, James Dolan, Arpita Kulshrestha, Mahmood Bilal, Kenneth D. Beaman, Sara Fleetwood, Gajendra K. Katara, Alice Gilman-Sachs
Rok vydání: 2020
Předmět:
0301 basic medicine
Cancer Research
Carcinogenesis
Nitric Oxide Synthase Type II
Cell Count
Ovarian tumor
0302 clinical medicine
Ovarian Neoplasms
biology
Caspase 3
Chemistry
Toll-Like Receptors
Antibodies
Monoclonal
a2 isoform
General Medicine
lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens
ovarian cancer
Oncology
030220 oncology & carcinogenesis
Cytokines
Molecular Medicine
Female
Inflammation Mediators
Antibody
Research Article
Vacuolar Proton-Translocating ATPases
Research Articsles
medicine.drug_class
Mice
Nude
Nitric Oxide
Monoclonal antibody
lcsh:RC254-282
03 medical and health sciences
Immune system
In vivo
Cell Line
Tumor
Genetics
medicine
Animals
Humans
Cell Proliferation
Macrophages
Immunity
Cancer
medicine.disease
030104 developmental biology
monoclonal antibody
Culture Media
Conditioned
Cancer cell
Leukocytes
Mononuclear
biology.protein
Cancer research
Neoplasm Grading
vacuolar‐ATPase
Ovarian cancer
Zdroj: Molecular Oncology
Molecular Oncology, Vol 14, Iss 10, Pp 2436-2454 (2020)
ISSN: 1878-0261
1574-7891
Popis: Tumor acidity is the key metabolic feature promoting cancer progression by eliciting immune‐suppression. V‐ATPases on a cancer cell's surface pump out excess protons and acidify the tumor microenvironment (TME). In vivo treatment of ovarian tumors using a monoclonal antibody (a2v‐mAb) directed against V‐ATPase‐V0a2 delays tumor growth by enhancing antitumor immune responses, making it an effective treatment strategy in ovarian cancer.
Tumor acidity is the key metabolic feature promoting cancer progression and is modulated by pH regulators on a cancer cell's surface that pump out excess protons/lactic acid for cancer cell survival. Neutralizing tumor acidity improves the therapeutic efficacy of current treatments including immunotherapies. Vacuolar‐ATPase (V‐ATPase) proton pumps encompass unique plasma membrane‐associated subunit isoforms, making this molecule an important target for anticancer therapy. Here, we examined the in vivo therapeutic efficacy of an antibody (a2v‐mAB) targeting specific V‐ATPase‐‘V0a2’ surface isoform in controlling ovarian tumor growth. In vitro a2v‐mAb treatment inhibited the proton pump activity in ovarian cancer (OVCA) cells. In vivo intraperitoneal a2v‐mAb treatment drastically delayed ovarian tumor growth with no measurable in vivo toxicity in a transplant tumor model. To explore the possible mechanism causing delayed tumor growth, histochemical analysis of the a2v‐mAb‐treated tumor tissues displayed high immune cell infiltration (M1‐macrophages, neutrophils, CD103+ cells, and NK cells) and an enhanced antitumor response (iNOS, IFN‐y, IL‐1α) compared to control. There was marked decrease in CA‐125‐positive cancer cells and an enhanced active caspase‐3 expression in a2v‐mAb‐treated tumors. RNA‐seq analysis of a2v‐mAb tumor tissues further revealed upregulation of apoptosis‐related and toll‐like receptor pathway‐related genes. Indirect coculture of a2v‐mAb‐treated OVCA cells with human PBMCs in an unbuffered medium led to an enhanced gene expression of antitumor molecules IFN‐y, IL‐17, and IL‐12‐A in PBMCs, further validating the in vivo antitumor responses. In conclusion, V‐ATPase inhibition using a monoclonal antibody directed against the V0a2 isoform increases antitumor immune responses and could therefore constitute an effective treatment strategy in OVCA.
Databáze: OpenAIRE
Externí odkaz: