title: NF-κB hyperactivation in tumor tissues allows tumor-selective reprogramming of the chemokine microenvironment to enhance the recruitment of cytolytic T effector cells.
abstract: Tumor infiltration with effector CD8(+) T cells (T(eff)) predicts longer recurrence-free survival in many types of human cancer, illustrating the broad significance of T(eff) for effective immunosurveillance. Colorectal tumors with reduced accumulation of T(eff) express low levels of T(eff)-attracting chemokines such as CXCL10/IP10 and CCL5/RANTES. In this study, we investigated the feasibility of enhancing tumor production of T(eff)-attracting chemokines as a cancer therapeutic strategy using a tissue explant culture system to analyze chemokine induction in intact tumor tissues. In different tumor explants, we observed highly heterogeneous responses to IFNα or poly-I:C (a TLR3 ligand) when they were applied individually. In contrast, a combination of IFNα and poly-I:C uniformly enhanced the production of CXCL10 and CCL5 in all tumor lesions. Moreover, these effects could be optimized by the further addition of COX inhibitors. Applying this triple combination also uniformly suppressed the production of CCL22/MDC, a chemokine associated with infiltration of T regulatory cells (T(reg)). The T(eff)-enhancing effects of this treatment occurred selectively in tumor tissues, as compared with tissues derived from tumor margins. These effects relied on the increased propensity of tumor-associated cells (mostly fibroblasts and infiltrating inflammatory cells) to hyperactivate NF-κB and produce T(eff)-attracting chemokines in response to treatment, resulting in an enhanced ability of the treated tumors to attract T(eff) cells and reduced ability to attract T(reg) cells. Together, our findings suggest the feasibility of exploiting NF-κB hyperactivation in the tumor microenvironment to selectively enhance T(eff) entry into colon tumors.
authors.affiliation: Department of Surgery, University of Pittsburgh Cancer Institute, Pittsburgh, PA 15213, USA.
authors.forename: Ravikumar
authors.initials: R
authors.lastname: Muthuswamy
authors.forename: Erik
authors.initials: E
authors.lastname: Berk
authors.forename: Beth Fallert
authors.initials: BF
authors.lastname: Junecko
authors.forename: Herbert J
authors.initials: HJ
authors.lastname: Zeh
authors.forename: Amer H
authors.initials: AH
authors.lastname: Zureikat
authors.forename: Daniel
authors.initials: D
authors.lastname: Normolle
authors.forename: The Minh
authors.initials: TM
authors.lastname: Luong
authors.forename: Todd A
authors.initials: TA
authors.lastname: Reinhart
authors.forename: David L
authors.initials: DL
authors.lastname: Bartlett
authors.forename: Pawel
authors.initials: P
authors.lastname: Kalinski
mesh_terms: D018938:Caco-2 Cells; D002277:Carcinoma / Q000235:genetics / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D002478:Cells, Cultured; D065150:Cellular Reprogramming / Q000235:genetics / Q000276:immunology / Q000502:physiology; D018925:Chemokines / Q000235:genetics / Q000378:metabolism*; D002634:Chemotaxis, Leukocyte / Q000235:genetics / Q000502:physiology; D015179:Colorectal Neoplasms / Q000235:genetics / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000502:physiology; D045325:HCT116 Cells; D019073:HT29 Cells; D061307:Human Umbilical Vein Endothelial Cells / Q000378:metabolism / Q000502:physiology; D006801:Humans; D008297:Male; D008875:Middle Aged; D016328:NF-kappa B / Q000819:agonists / Q000378:metabolism* / Q000502:physiology; D009369:Neoplasms / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D009928:Organ Specificity / Q000276:immunology; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology / Q000378:metabolism / Q000502:physiology*; D059016:Tumor Microenvironment / Q000502:physiology; D015854:Up-Regulation / Q000235:genetics / Q000276:immunology
chemical_list: D018925:Chemokines; D016328:NF-kappa B