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.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA048080-06
Application #
2007735
Study Section
Experimental Therapeutics Subcommittee 1 (ET)
Program Officer
Kelsey, Morris I
Project Start
1990-08-06
Project End
1998-11-30
Budget Start
1996-12-05
Budget End
1998-11-30
Support Year
6
Fiscal Year
1997
Total Cost
Indirect Cost
Name
Loyola University Chicago
Department
Pathology
Type
Schools of Medicine
DUNS #
791277940
City
Maywood
State
IL
Country
United States
Zip Code
60153
Wiers, K M; Lathers, D M; Wright, M A et al. (2000) Vitamin D3 treatment to diminish the levels of immune suppressive CD34+ cells increases the effectiveness of adoptive immunotherapy. J Immunother 23:115-24
Pandit, R; Lathers, D M; Beal, N M et al. (2000) CD34+ immune suppressive cells in the peripheral blood of patients with head and neck cancer. Ann Otol Rhinol Laryngol 109:749-54
Lathers, D M; Lubbers, E; Wright, M A et al. (1999) Dendritic cell differentiation pathways of CD34+ cells from the peripheral blood of head and neck cancer patients. J Leukoc Biol 65:623-8
Gabel, S; Benefield, J; Meisinger, J et al. (1999) Protein phosphatases 1 and 2A maintain endothelial cells in a resting state, limiting the motility that is needed for the morphogenic process of angiogenesis. Otolaryngol Head Neck Surg 121:463-8
Young, M R; Lathers, D M (1999) Myeloid progenitor cells mediate immune suppression in patients with head and neck cancers. Int J Immunopharmacol 21:241-52
Lathers, D M; Lubbers, E; Beal, N M et al. (1999) Cultures derived from peripheral blood CD34+ progenitor cells of head and neck cancer patients and from cord blood are functionally different. Hum Immunol 60:1207-15
Wright, M A; Wiers, K; Vellody, K et al. (1998) Stimulation of immune suppressive CD34+ cells from normal bone marrow by Lewis lung carcinoma tumors. Cancer Immunol Immunother 46:253-60
Wiers, K; Wright, M A; Vellody, K et al. (1998) Failure of tumor-reactive lymph node cells to kill tumor in the presence of immune-suppressive CD34+ cells can be overcome with vitamin D3 treatment to diminish CD34+ cell levels. Clin Exp Metastasis 16:275-82
Jackson, J; Meisinger, J; Patel, S et al. (1997) Protein phosphatase-2A associates with the cytoskeleton to maintain cell spreading and reduced motility of nonmetastatic Lewis lung carcinoma cells: the loss of this regulatory control in metastatic cells. Invasion Metastasis 17:199-209
Young, M R; Lozano, Y (1997) Inhibition of tumor invasiveness by 1alpha,25-dihydroxyvitamin D3 coupled to a decline in protein kinase A activity and an increase in cytoskeletal organization. Clin Exp Metastasis 15:102-10

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