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.

Chemokine nitration prevents intratumoral infiltration of antigen-specific T cells

LAZZARATO, Loretta;FRUTTERO, Roberta;GASCO, Alberto;
2011

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.
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TUMOR; PROSTATE-CANCER; IMMUNE-RESPONSES; COLORECTAL-CANCER; TYROSINE NITRATION; IN-VIVO; CANCER-IMMUNOTHERAPY; MYELOID SUPPRESSOR-CELLS; MONOCYTE CHEMOTACTIC PROTEIN-1
Barbara Molon; Stefano Ugel; Federica Del Pozzo; Cristiana Soldani; Serena Zilio; Debora Avella; Antonella De Palma; PierLuigi Mauri; Ana Monegal; Maria Rescigno; Benedetta Savino; Piergiuseppe Colombo; Nives Jonjic; Sanja Pecanic; Loretta Lazzarato; Roberta Fruttero; Alberto Gasco; Vincenzo Bronte; Antonella Viola
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2318/133732
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