NF-κB in Stromal Cells Help Cancers Evade Anti-tumor Immunity
Abstract
ObjectiveThe tumor-microenvironment(TME) actively modulates growth of cancer cells. NF-kB is a major pro-proliferative pathway in cancer cells but it’s role is unclear in the TME. We aim to study tumor growth when stromal... [ view full abstract ]
Objective
The tumor-microenvironment(TME) actively modulates growth of cancer cells. NF-kB is a major pro-proliferative pathway in cancer cells but it’s role is unclear in the TME. We aim to study tumor growth when stromal NFKB (p50) is specifically deleted.
Methods
Cancer cells derived from a spontaneous genetic model of pancreatic cancer, Pdx1-Cre;K-Ras+/LSLG12D;p53R172H/+ (KPC), were surgically co-injected in the pancreas of mice with stellate cells with(WT PSC) or without functional NF-kB(p50-/- PSC). This was repeated in immuno-deficient mice or mice with depleted CD8 cells to ascertain if the effect of stromal NF-kB was mediated via the immune system. Similarly, syngeneic cancer cell lines of melanoma(B16-F10) and Lung Cancer(Lewis Lung Cancer) were co-injected with WT or NF-kB deficient fibroblasts. Immune infiltration in the ex-vivo tumor samples were analyzed by flow cytometry.
Results
Cancer cells that were grown NF-kB deficient stromal cells formed smaller tumors compared to stromal cells with intact NF-kB. This effect was also observed in syngeneic melanoma and lung tumors. Tumors co-injected with NF-kB deficient stellate cells had greater infiltration of CD8+ cytotoxic T cells. When tumors were grown in mice lacking a functional immune system or on depletion of CD8 cells, the tumor inhibitory effect of NF-kB deficient stellate cells was lost suggesting that the effect was mediated via a functional immune system.
Conclusion
Stromal cells deficient in NF-kB mediate an anti-tumorigenic stimulus to cancer cells by protecting against immune mediated cytotoxicity. Modulation of this pathway in stromal cells may hold therapeutic promise in treating pancreatic cancer.
Authors
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Bhuwan Giri
(University of Miami – Miller School of Medicine, Miami, Florida, USA)
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Bharti Garg
(University of Miami – Miller School of Medicine, Miami, Florida, USA)
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Vrishketan Sethi
(University of Miami – Miller School of Medicine, Miami, Florida, USA)
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Shrey Modi
(University of Miami – Miller School of Medicine, Miami, Florida, USA)
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Sundaram Ramakrishnan
(University of Miami – Miller School of Medicine, Miami, Florida, USA)
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Sulagna Banerjee
(University of Miami – Miller School of Medicine, Miami, Florida, USA)
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Ashok Saluja
(University of Miami – Miller School of Medicine, Miami, Florida, USA)
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Vikas Dudeja
(University of Miami Leonard M. Miller School of Medicine, Miami, Florida, U.S.A.)
Topic Area
Surgical Oncology
Session
QS-SurgOnc » Quick-Shot Presentations: Surgical Oncology (15:00 - Thursday, 21st September, Lee 404)