B. Giri1, B. Garg1, S. Modi1, V. Sethi1, S. Ramakrishnan1, S. Banerjee1, A. Saluja1, V. Dudeja1 1University Of Miami,Miami, FL, USA
Introduction: While the role of NFκB in tumor cells in cancer cell growth and metastases is well established, the impact of NFκB in tumor stroma on pancreatic cancer growth is unknown. We sought to understand the effect of depletion of p50 subunit of NFκB in the stromal cells on pancreatic cancer growth and metastases.
Methods: Pancreatic cancer cells isolated from spontaneous tumors developing in Pdx1-Cre;K-Ras+/LSLG12D;p53R172H/+ (KPC) mice were surgically co-injected with either wild-type (WT) or p50-/- (thus lacking p50 subunit of NFκB) pancreatic stellate cells (PSC). The impact of lack of p50 subunit of NFκB on tumor growth and metastases was measured. This model was repeated in athymic nude mice lacking a functional immune system to assess the effect of p50-/- PSC on tumor cells in the absence of adaptive immunity. The impact of deletion of p50 subunit of NFκB in stroma cells on growth of melanoma (B16-F10) and Lung Cancer (Lewis Lung Cancer) was also evaluated. Immune infiltration in the ex-vivo tumor samples were analyzed by flow cytometry.
Results:Cancer cells co-injected with p50-/- stellate cells formed smaller tumors compared to WT PSC. This was also observed in B16-F10 as well as the Lewis Lung Cancer model. On analysis by flow cytometry, tumors co-injected with p50-/- stellate cells had a higher infiltration of CD8+ cells. Interestingly, the tumor inhibitory effect of p50-/- stellate cells was lost when KPC cells were grown with p50-/- PSC in immuno-deficient athymic nude mice suggesting that stromal cells in the presence of p50 -/- may function to protect cancer cells from an immune mediated attack.
Conclusion:Tumor stroma protects cancer cells from immune-mediated cytotoxicity in NFκB dependent fashion. Developing strategies to downregulate NFκB in tumor stroma may lead to an anti-tumor effect, alone or in combination with immunomodulatory strategies.
