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

Abstract

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.

• Authors: Arpita Kulshrestha, Gajendra K Katara, Safaa A Ibrahim, Valerie E Riehl, Sylvia Schneiderman, Mahmood Bilal, Alexandria N Young, Shayna Levine, Sara Fleetwood, James Dolan, Alice Gilman-Sachs, Kenneth D Beaman
• Journal: Molecular oncology (Mol Oncol) Vol. 14 Issue 10 Pg. 2436-2454 (10 2020) ISSN: 1878-0261 [Electronic] United States
• PMID: 32797726 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2020 The Authors. Published by FEBS Press and John Wiley & Sons Ltd.

Chemical References

• Antibodies, Monoclonal
• Culture Media, Conditioned
• Cytokines
• Inflammation Mediators
• Toll-Like Receptors
• Nitric Oxide
• Nitric Oxide Synthase Type II
• Caspase 3
• Vacuolar Proton-Translocating ATPases

Topics

• Animals
• Antibodies, Monoclonal (pharmacology)
• Carcinogenesis (drug effects, pathology)
• Caspase 3 (metabolism)
• Cell Count
• Cell Line, Tumor
• Cell Proliferation
• Culture Media, Conditioned (pharmacology)
• Cytokines (genetics, metabolism)
• Female
• Humans
• Immunity
• Inflammation Mediators (metabolism)
• Leukocytes, Mononuclear (drug effects, metabolism)
• Macrophages (drug effects, metabolism)
• Mice, Nude
• Neoplasm Grading
• Nitric Oxide (metabolism)
• Nitric Oxide Synthase Type II (metabolism)
• Ovarian Neoplasms (immunology, pathology)
• Toll-Like Receptors (metabolism)
• Vacuolar Proton-Translocating ATPases (antagonists & inhibitors, metabolism)