title: Cancer acidity: An ultimate frontier of tumor immune escape and a novel target of immunomodulation.
abstract: The link between cancer metabolism and immunosuppression, inflammation and immune escape has generated major interest in investigating the effects of low pH on tumor immunity. Indeed, microenvironmental acidity may differentially impact on diverse components of tumor immune surveillance, eventually contributing to immune escape and cancer progression. Although the molecular pathways underlying acidity-related immune dysfunctions are just emerging, initial evidence indicates that antitumor effectors such as T and NK cells tend to lose their function and undergo a state of mostly reversible anergy followed by apoptosis, when exposed to low pH environment. At opposite, immunosuppressive components such as myeloid cells and regulatory T cells are engaged by tumor acidity to sustain tumor growth while blocking antitumor immune responses. Local acidity could also profoundly influence bioactivity and distribution of antibodies, thus potentially interfering with the clinical efficacy of therapeutic antibodies including immune checkpoint inhibitors. Hence tumor acidity is a central regulator of cancer immunity that orchestrates both local and systemic immunosuppression and that may offer a broad panel of therapeutic targets. This review outlines the fundamental pathways of acidity-driven immune dysfunctions and sheds light on the potential strategies that could be envisaged to potentiate immune-mediated tumor control in cancer patients.
authors.affiliation: Unit of Immunotherapy of Human Tumors, Department of Experimental Oncology and Molecular Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, Via Venezian 1, 20133 Milan, Italy. Electronic address: veronica.huber@istitutotumori.mi.it.
authors.forename: Veronica
authors.initials: V
authors.lastname: Huber
authors.affiliation: Unit of Immunotherapy of Human Tumors, Department of Experimental Oncology and Molecular Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, Via Venezian 1, 20133 Milan, Italy.
authors.forename: Chiara
authors.initials: C
authors.lastname: Camisaschi
authors.affiliation: Unit of Immunotherapy of Human Tumors, Department of Experimental Oncology and Molecular Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, Via Venezian 1, 20133 Milan, Italy.
authors.forename: Angela
authors.initials: A
authors.lastname: Berzi
authors.affiliation: Unit of Immunotherapy of Human Tumors, Department of Experimental Oncology and Molecular Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, Via Venezian 1, 20133 Milan, Italy.
authors.forename: Simona
authors.initials: S
authors.lastname: Ferro
authors.affiliation: Department of Oncology and Molecular Medicine, National Institute of Health, Viale Regina Elena 299, 00161 Rome, Italy.
authors.forename: Luana
authors.initials: L
authors.lastname: Lugini
authors.affiliation: Molecular Targeting Unit, Department of Experimental Oncology and Molecular Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, Via Amadeo 42, 20133 Milan, Italy.
authors.forename: Tiziana
authors.initials: T
authors.lastname: Triulzi
authors.affiliation: Unit of Immunotherapy of Human Tumors, Department of Experimental Oncology and Molecular Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, Via Venezian 1, 20133 Milan, Italy.
authors.forename: Alessandra
authors.initials: A
authors.lastname: Tuccitto
authors.affiliation: Molecular Targeting Unit, Department of Experimental Oncology and Molecular Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, Via Amadeo 42, 20133 Milan, Italy.
authors.forename: Elda
authors.initials: E
authors.lastname: Tagliabue
authors.affiliation: Unit of Immunotherapy of Human Tumors, Department of Experimental Oncology and Molecular Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, Via Venezian 1, 20133 Milan, Italy.
authors.forename: Chiara
authors.initials: C
authors.lastname: Castelli
authors.affiliation: Unit of Immunotherapy of Human Tumors, Department of Experimental Oncology and Molecular Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, Via Venezian 1, 20133 Milan, Italy.
authors.forename: Licia
authors.initials: L
authors.lastname: Rivoltini
mesh_terms: D000143:Acids / Q000378:metabolism*; D006801:Humans; D006863:Hydrogen-Ion Concentration; D009369:Neoplasms / Q000276:immunology / Q000378:metabolism*; D019139:Tumor Escape
chemical_list: D000143:Acids
keywords: Acidity; Cancer; Glycolysis; Hypoxia; Immune checkpoints; Immunity; Immunosurveillance; Immunotherapy; Lactate; Myeloid-derived suppressor cells; Regulatory T cells; Therapeutic antibodies; Tumor microenvironment; pH