Article

NF-kappa B Hyperactivation in Tumor Tissues Allows Tumor-Selective Reprogramming of the Chemokine Microenvironment to Enhance the Recruitment of Cytolytic T Effector Cells

Department of Surgery, University of Pittsburgh Cancer Institute, Pittsburgh, PA 15213, USA.
Cancer Research (Impact Factor: 9.28). 05/2012; 72(15):3735-43. DOI: 10.1158/0008-5472.CAN-11-4136
Source: PubMed

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.

0 Followers
 · 
124 Views
  • Source
    • "Select chemokines and their corresponding receptors have been shown to play a role in the recruitment of specific T cell subsets into tumors and sites of inflammation ( Sallusto et al . , 1997 , 1998 ; Bonecchi et al . , 1998 ; Loetscher et al . , 1998 ; Hirai et al . , 2001 ; Iellem et al . , 2001 ; Muthuswamy et al . , 2012 ) . Among human TReg cells , the chemokine receptor CCR4 , and its ligands CCL22 and CCL17 , are believed to be the most predominant chemokine - related mechanism responsible for TReg cell trafficking to tumors ( Iellem et al . , 2001 ) . It has been reported that production of the chemokine CCL22 is associated with human ovarian cancer"
    [Show abstract] [Hide abstract]
    ABSTRACT: The importance of CD4 T cells in orchestrating the immune system and their role in inducing effective T cell-mediated therapies for the treatment of patients with select established malignancies are undisputable. Through a complex and balanced array of direct and indirect mechanisms of cellular activation and regulation, this functionally diverse family of lymphocytes can potentially promote tumor eradication, long-term tumor immunity, and aid in establishing and/or rebalancing immune cell homeostasis through interaction with other immune cell populations within the highly dynamic tumor environment. However, recent studies have uncovered additional functions and roles for CD4 T cells, some of which are independent of other lymphocytes, that can not only influence and contribute to tumor immunity but paradoxically promote tumor growth and progression. Here, we review the recent advances in our understanding of the various CD4 T cell lineages and their signature cytokines in disease progression and/or regression. We discuss their direct and indirect mechanistic interplay among themselves and with other responding cells of the antitumor response, their potential roles and abilities for "plasticity" and memory cell generation within the hostile tumor environment, and their potentials in cancer treatment and immunotherapy.
    Frontiers in Oncology 03/2013; 3:63. DOI:10.3389/fonc.2013.00063
  • [Show abstract] [Hide abstract]
    ABSTRACT: To review the current understanding of the underlying molecular, biologic, and genetic mechanisms involved in ovarian cancer development and how these mechanisms can be targets for prevention, detection, and treatment of the disease and its recurrence. In May 2012, we convened a meeting of researchers, clinicians, and consumer advocates to review the state of current knowledge on molecular mechanisms and identify fruitful areas for further investigations. The meeting consisted of 7 scientific sessions ranging from Epidemiology, Early Detection, and Biology to Therapeutics and Quality of Life. Sessions consisted of talks and panel discussions by international leaders in ovarian cancer research. A special career development session by the Congressionally Directed Medical Research Program Department of Defense Ovarian Cancer Academy as well as an oral abstract and poster session showcased promising new research by junior scientists. Technological advances in the last decade have increased our knowledge of the molecular mechanisms involved in a host of biological activities related to ovarian cancer. Understanding the role these mechanisms play in cancer initiation and progression will help lead to the development of prevention and treatment modalities that can be personalized to each patient, thereby helping to overcome this highly fatal malignancy.
    International Journal of Gynecological Cancer 10/2012; 22(8):S45-57. DOI:10.1097/IGC.0b013e31826bd1f2 · 1.95 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: The 27th annual meeting of the Society for Immunotherapy of Cancer (SITC) was held on October 26–28, 2012 in North Bethesda, Maryland and the highlights of the meeting are summarized. The topics covered at this meeting included advances in cancer treatment using adoptive cell therapy (ACT), oncolytic viruses, dendritic cells (DCs), immune check point modulators and combination therapies. Advances in immune editing of cancer, immune modulation by cancer and the tumor microenvironment were also discussed as were advances in single cell analysis and the manufacture and potency testing of tumor infiltrating lymphocytes (TIL).
    05/2013; 1(1). DOI:10.1186/2051-1426-1-4
Show more