Abstract
In an orthotopic murine model of head and neck squamous cell carcinoma (SCC VII/SF) we studied NK cell-mediated immunity following vaccination with a recombinant vaccinia virus expressing IL-2 (rvv-IL-2). SCC VII/SF tumor cells were injected into the oral cavity of C3H/HeJ mice on day 0. Mice were vaccinated on days 7, 10, and 14 with rvv-IL-2 and control vaccines. Phenotypes, numbers, and biological activities of NK cells were determined following vaccination. Levels of expression of NK-activating receptor NKG2D and CD16 on NK cell surface were assayed in the vaccinated mice. Expression of NKG2D ligands, Rae1, and H60 on SCC VII/SF cells was also examined. Vaccination with rvv-IL-2 resulted in expansion of NK cells. NK cells isolated from rvv-IL-2-vaccinated mice had significantly higher biological activities compared with mice treated with control vaccines. NK cells from tumor-bearing mice expressed significantly lower levels of NKG2D and CD16 compared with rvv-IL-2 vaccinated mice. SCC VII/SF tumors expressed NKG2D ligand Rae 1, although H60 was not present. SCC VII/SF tumors expressed high levels of TGF-beta1, which were down-modulated by vaccination with rvv-IL-2. Incubation of NK cells with tumor homogenate or cultured supernatant of SCC VII/SF cells reduced the expression of NKG2D and CD16. This inhibition appeared to be mediated by TGF-beta1. SCC VII/SF tumors in the oral cavity of the mice secrete high quantities of TGF-beta1, which reduce the expression of NK cell receptor NKG2D as well as CD16 and inhibits biological functions of NK cells.
Highlights
Continuous production of IL-2 at the tumor site may be more effective for the treatment of HNSCC patients
We have demonstrated that intratumoral injection of recombinant vaccinia virus expressing IL-2 led to the synthesis of IL-2 at the tumor site, which lasted for ϳ7 days [7]
In an earlier study using this model we demonstrated that a combined s.c. and intratumoral vaccination with rvv-IL-2 resulted in enhanced survival and tumor regression compared with intratumoral rvv-IL-2 injection alone [11]
Summary
Continuous production of IL-2 at the tumor site may be more effective for the treatment of HNSCC patients. We have demonstrated that intratumoral injection of recombinant vaccinia virus (rvv) expressing IL-2 (rvv-IL-2) led to the synthesis of IL-2 at the tumor site, which lasted for ϳ7 days [7]. We demonstrated the antitumor efficacy of rvv expressing the cytokines GM-CSF and IL-2 in a number of animal models (7, 9 –14). Because HNSCC patients are severely immunocompromised, we are exploring the potential of this vaccine in an orthotopic murine model of head and neck cancer (SCC VII/SF). INHIBITION OF NK CELL ACTIVITY BY TGF-1 humans are MHC class I-related chain A and chain B and H60/Rae in mice. We studied the role of NK cells, NKG2D expression, and the effect of TGF-1 on NK cells in this murine model of HNSCC. Tumors from untreated mice expressed high levels of TGF-1, which appear to inactivate NK cell activities by down-regulation of NKG2D and CD16
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