title: Tumor-infiltrating myeloid cells induce tumor cell resistance to cytotoxic T cells in mice.
abstract: Cancer immunotherapeutic approaches induce tumor-specific immune responses, in particular CTL responses, in many patients treated. However, such approaches are clinically beneficial to only a few patients. We set out to investigate one possible explanation for the failure of CTLs to eliminate tumors, specifically, the concept that this failure is not dependent on inhibition of T cell function. In a previous study, we found that in mice, myeloid-derived suppressor cells (MDSCs) are a source of the free radical peroxynitrite (PNT). Here, we show that pre-treatment of mouse and human tumor cells with PNT or with MDSCs inhibits binding of processed peptides to tumor cell-associated MHC, and as a result, tumor cells become resistant to antigen-specific CTLs. This effect was abrogated in MDSCs treated with a PNT inhibitor. In a mouse model of tumor-associated inflammation in which the antitumor effects of antigen-specific CTLs are eradicated by expression of IL-1β in the tumor cells, we determined that therapeutic failure was not caused by more profound suppression of CTLs by IL-1β-expressing tumors than tumors not expressing this proinflammatory cytokine. Rather, therapeutic failure was a result of the presence of PNT. Clinical relevance for these data was suggested by the observation that myeloid cells were the predominant source of PNT in human lung, pancreatic, and breast cancer samples. Our data therefore suggest what we believe to be a novel mechanism of MDSC-mediated tumor cell resistance to CTLs.
authors.affiliation: Department of Immunology, H. Lee Moffitt Cancer Center, Tampa, Florida 33612, USA.
authors.forename: Tangying
authors.initials: T
authors.lastname: Lu
authors.forename: Rupal
authors.initials: R
authors.lastname: Ramakrishnan
authors.forename: Soner
authors.initials: S
authors.lastname: Altiok
authors.forename: Je-In
authors.initials: JI
authors.lastname: Youn
authors.forename: Pingyan
authors.initials: P
authors.lastname: Cheng
authors.forename: Esteban
authors.initials: E
authors.lastname: Celis
authors.forename: Vladimir
authors.initials: V
authors.lastname: Pisarev
authors.forename: Simon
authors.initials: S
authors.lastname: Sherman
authors.forename: Michael B
authors.initials: MB
authors.lastname: Sporn
authors.forename: Dmitry
authors.initials: D
authors.lastname: Gabrilovich
mesh_terms: D000818:Animals; D018827:Carcinoma, Lewis Lung / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D005260:Female; D006801:Humans; D018836:Inflammation Mediators / Q000378:metabolism; D053583:Interleukin-1beta / Q000378:metabolism; D016246:Lymphocytes, Tumor-Infiltrating / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D008981:Molsidomine / Q000031:analogs & derivatives / Q000494:pharmacology; D022423:Myeloid Cells / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D009374:Neoplasms, Experimental / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D030421:Peroxynitrous Acid / Q000378:metabolism / Q000494:pharmacology; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*; D019139:Tumor Escape / Q000187:drug effects / Q000276:immunology* / Q000502:physiology
chemical_list: D018836:Inflammation Mediators; D053583:Interleukin-1beta; D030421:Peroxynitrous Acid; C002385:linsidomine; D008981:Molsidomine