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.
|Titolo:||Chemokine nitration prevents intratumoral infiltration of antigen-specific T cells|
|Parole Chiave:||Protein Processing, Post-Translational; Tumor Microenvironment; Adoptive Transfer; Animals; Cell Line, Tumor; Cell Movement; Chemokine CCL2; Chemokine CXCL12; Colorectal Neoplasms; Humans; Immunotherapy; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Reactive Nitrogen Species; T-Lymphocyte Subsets; T-Lymphocytes, Cytotoxic|
|Settore Scientifico Disciplinare:||Settore MED/04 - Patologia Generale|
|Data di pubblicazione:||26-set-2011|
|Digital Object Identifier (DOI):||10.1084/jem.20101956|
|Appare nelle tipologie:||01 - Articolo su periodico|