title: Chemokine nitration prevents intratumoral infiltration of antigen-specific T cells.
abstract: Tumor-promoted constraints negatively affect cytotoxic T lymphocyte (CTL) trafficking to the tumor core and, as a result, inhibit tumor killing. The production of reactive nitrogen species (RNS) within the tumor microenvironment has been reported in mouse and human cancers. We describe a novel RNS-dependent posttranslational modification of chemokines that has a profound impact on leukocyte recruitment to mouse and human tumors. Intratumoral RNS production induces CCL2 chemokine nitration and hinders T cell infiltration, resulting in the trapping of tumor-specific T cells in the stroma that surrounds cancer cells. Preconditioning of the tumor microenvironment with novel drugs that inhibit CCL2 modification facilitates CTL invasion of the tumor, suggesting that these drugs may be effective in cancer immunotherapy. Our results unveil an unexpected mechanism of tumor evasion and introduce new avenues for cancer immunotherapy.
authors.affiliation: Istituto Oncologico Veneto, Istituti di Ricovero e Cura a Carattere Scientifico (IRCCS) Venetian Oncological Institute, 35128 Padua, Italy. barbara.molon@unipd.it
authors.forename: Barbara
authors.initials: B
authors.lastname: Molon
authors.forename: Stefano
authors.initials: S
authors.lastname: Ugel
authors.forename: Federica
authors.initials: F
authors.lastname: Del Pozzo
authors.forename: Cristiana
authors.initials: C
authors.lastname: Soldani
authors.forename: Serena
authors.initials: S
authors.lastname: Zilio
authors.forename: Debora
authors.initials: D
authors.lastname: Avella
authors.forename: Antonella
authors.initials: A
authors.lastname: De Palma
authors.forename: Pierluigi
authors.initials: P
authors.lastname: Mauri
authors.forename: Ana
authors.initials: A
authors.lastname: Monegal
authors.forename: Maria
authors.initials: M
authors.lastname: Rescigno
authors.forename: Benedetta
authors.initials: B
authors.lastname: Savino
authors.forename: Piergiuseppe
authors.initials: P
authors.lastname: Colombo
authors.forename: Nives
authors.initials: N
authors.lastname: Jonjic
authors.forename: Sanja
authors.initials: S
authors.lastname: Pecanic
authors.forename: Loretta
authors.initials: L
authors.lastname: Lazzarato
authors.forename: Roberta
authors.initials: R
authors.lastname: Fruttero
authors.forename: Alberto
authors.initials: A
authors.lastname: Gasco
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Bronte
authors.forename: Antonella
authors.initials: A
authors.lastname: Viola
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000276:immunology; D018932:Chemokine CCL2 / Q000276:immunology*; D054377:Chemokine CXCL12; D015179:Colorectal Neoplasms / Q000276:immunology / Q000473:pathology; D006801:Humans; D007167:Immunotherapy / Q000379:methods; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D011499:Protein Processing, Post-Translational; D026361:Reactive Nitrogen Species / Q000276:immunology*; D016176:T-Lymphocyte Subsets / Q000276:immunology*; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*; D059016:Tumor Microenvironment
chemical_list: D018932:Chemokine CCL2; D054377:Chemokine CXCL12; D026361:Reactive Nitrogen Species