Human cancers can elicit anti-cancer immune reactivity, but cancer patients have defects in their immune functions and are poorly reactive to the cancer and to immune stimulatory cancer therapies such as IL-2. We have shown that production of granulocyte-macrophage colony-stimulating factor (GM-CSF) by murine Lewis lung carcinoma (LLC) tumors induces immune suppressive GM-progenitor cells which can be eliminated with myeloid differentiation therapy composed by low-dose interferon-gamma (IFN-gamma) plus tumor necrosis factor-alpha (TNF-alpha). In vivo, this leads to immune restoration, increased responsiveness to immune stimulatory IL-2 therapy, and reduced metastasis. Recently we showed that a high number (>50%) of human lung and head and neck cancers secrete GM-CSF and contain cells resembling GM-progenitor cells (CD34+) that block reactivity of the tumor-infiltrating lymphocytes (TIL) to immune stimulation. These results provide the rationale for suggesting that such suppressor cells might inhibit responsiveness of cancer patients to immune stimulatory cancer therapies. The hypothesis of this study is that immune suppressive GM-progenitor cells are within GM-CSF-secreting human cancers and that their elimination will increase immune responsiveness to autologous cancer and to immune stimulatory cancer therapies. This will first be tested in vitro with the use of human cancer and regional lymph node specimens.
The first aim will identify and characterize GM-suppressor cells in human lung cancers and head and neck cancers that secrete GM-CSF.
The second aim will be to eliminate GM-suppressor cells from GM-CSF-secreting human cancers with the use of myeloid differentiation treatment so as to restore responsiveness of the immune infiltrate to IL-2 and, ultimately, to autologous cancer. The in vivo effectiveness of myeloid differentiation therapy at restoring responsiveness to immune stimulatory therapies will be tested in an intrabronchial LLC mouse model and in a LLC tumor excision model, both of which reflect many of the properties of human lung cancers. Thus, the third aim will determine if eliminating GM-suppressor cells with myeloid differentiation therapy increases immune infiltration and activation in the tumor and increases responsiveness to immune stimulatory IL-2 therapy.
The fourth aim i s to increase the anti-tumor effectiveness of adoptive tumor-infiltrating lymphocyte (TIL) immunotherapy in LLC-bearing mice by eliminating GM-suppressor cells with myeloid differentiation therapy. The clinical significance of this study is that it will first define a previously overlooked GM-CSF-stimulated immune subversive mechanism that is highly prevalent in lung and head and neck cancers (>50% of the cancers we have tested). This study will then test a non-toxic therapy to eliminate these suppressor cells and, in turn, increase responsiveness to immune stimulatory anti-cancer therapies.
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