NF-κB hyperactivation in tumor tissues allows tumor-selective reprogramming of the chemokine microenvironment to enhance the recruitment of cytolytic T effector cells

Ravikumar Muthuswamy, Erik Berk, Beth Fallert Junecko, Herbert J. Zeh, Amer H. Zureikat, Daniel Normolle, The Minh Luong, Todd A. Reinhart, David L. Bartlett, Pawel Kalinski

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Abstract

Tumor in filtration 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 in filtration 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 in filtrating 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.

Original languageEnglish (US)
Pages (from-to)3735-3743
Number of pages9
JournalCancer Research
Volume72
Issue number15
DOIs
StatePublished - Aug 1 2012

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ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Muthuswamy, R., Berk, E., Junecko, B. F., Zeh, H. J., Zureikat, A. H., Normolle, D., Luong, T. M., Reinhart, T. A., Bartlett, D. L., & Kalinski, P. (2012). NF-κB hyperactivation in tumor tissues allows tumor-selective reprogramming of the chemokine microenvironment to enhance the recruitment of cytolytic T effector cells. Cancer Research, 72(15), 3735-3743. https://doi.org/10.1158/0008-5472.CAN-11-4136