Targeting Immune Regulatory Networks to Counteract Immune Suppression in Cancer.
The onset of cancer is unavoidably accompanied by suppression of antitumor immunity. This occurs through mechanisms ranging from the progressive accumulation of regulatory immune cells associated with chronic immune stimulation and inflammation, to the expression of immunosuppressive molecules. Some of them are being successfully exploited as therapeutic targets, with impressive clinical results achieved in patients, as in the case of immune checkpoint inhibitors. To limit immune attack, tumor cells exploit specific pathways to render the tumor microenvironment hostile for antitumor effector cells. Local acidification might, in fact, anergize activated T cells and facilitate the accumulation of immune suppressive cells. Moreover, the release of extracellular vesicles by tumor cells can condition distant immune sites contributing to the onset of systemic immune suppression. Understanding which mechanisms may be prevalent in specific cancers or disease stages, and identifying possible strategies to counterbalance would majorly contribute to improving clinical efficacy of cancer immunotherapy. Here, we intend to highlight these mechanisms, how they could be targeted and the tools that might be available in the near future to achieve this goal.
Unit of Immunotherapy of Human Tumors, Fondazione IRCCS Istituto Nazionale dei Tumori, 20133 Milan, Italy. chiara.camisaschi@istitutotumori.mi.it.
Chiara
C
Camisaschi
Unit of Immunotherapy of Human Tumors, Fondazione IRCCS Istituto Nazionale dei Tumori, 20133 Milan, Italy. viviana.vallacchi@istitutotumori.mi.it.
Viviana
V
Vallacchi
Unit of Immunotherapy of Human Tumors, Fondazione IRCCS Istituto Nazionale dei Tumori, 20133 Milan, Italy. elisabetta.vergani@istitutotumori.mi.it.
Elisabetta
E
Vergani
Unit of Immunotherapy of Human Tumors, Fondazione IRCCS Istituto Nazionale dei Tumori, 20133 Milan, Italy. marcella.tazzari@radboudumc.nl.
Marcella
M
Tazzari
Unit of Immunotherapy of Human Tumors, Fondazione IRCCS Istituto Nazionale dei Tumori, 20133 Milan, Italy. simona.ferro@istitutotumori.mi.it.
Simona
S
Ferro
Unit of Immunotherapy of Human Tumors, Fondazione IRCCS Istituto Nazionale dei Tumori, 20133 Milan, Italy. alessandra.tuccitto@istitutotumori.mi.it.
Alessandra
A
Tuccitto
Mount Sinai Liver Cancer Program, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA. olga.kuchuk@mssm.edu.
Olga
O
Kuchuk
Unit of Immunotherapy of Human Tumors, Fondazione IRCCS Istituto Nazionale dei Tumori, 20133 Milan, Italy. eriomina.shahaj@istitutotumori.mi.it.
Eriomina
E
Shahaj
Unit of Immunotherapy of Human Tumors, Fondazione IRCCS Istituto Nazionale dei Tumori, 20133 Milan, Italy. roberta.sulsenti@istitutotumori.mi.it.
Roberta
R
Sulsenti
Unit of Immunotherapy of Human Tumors, Fondazione IRCCS Istituto Nazionale dei Tumori, 20133 Milan, Italy. chiara.castelli@istitutotumori.mi.it.
Chiara
C
Castelli
Unit of Immunotherapy of Human Tumors, Fondazione IRCCS Istituto Nazionale dei Tumori, 20133 Milan, Italy. monica.rodolfo@istitutotumori.mi.it.
Monica
M
Rodolfo
Unit of Immunotherapy of Human Tumors, Fondazione IRCCS Istituto Nazionale dei Tumori, 20133 Milan, Italy. licia.rivoltini@istitutotumori.mi.it.
Licia
L
Rivoltini
Unit of Immunotherapy of Human Tumors, Fondazione IRCCS Istituto Nazionale dei Tumori, 20133 Milan, Italy. veronica.huber@istitutotumori.mi.it.
Veronica
V
Huber
cancer; extracellular vesicles; immune suppression; myeloid-derived suppressor cells; regulatory T cells; therapy; tumor acidity