Tumor-induced macrophage and T cell dysfunction

Macrophages (MΦ) and T cells mediate helper, effector, and cytotoxic activities. Tumor growth changes the phenotypic and functional characteristics of MΦ and T cells and shifts them toward suppressor phenotypes and functional activities. Tumor growth changed MΦ DNA synthesis when activated through Mac-1 and Mac-3 surface molecules, which suggests that specific receptor-ligand interactions modulate MΦ cell-cycle kinetics differently in the tumor-bearing host (TBH). Tumor growth changed MΦ responsiveness to MΦ colony-stimulating factor (M-CSF). M-CSF did not reverse decreases in autorecognition caused by TBH MΦ, and increased TBH MΦ suppression during T-cell alloreactivity. TBH suppressor activities were associated predominantly with MHC class II MΦ. TBH class II⁻ MΦ quantitatively and qualitatively suppressed T-cell autoreactivity partly by dysregulation of interferon-gamma (IFN-y), interleukin-4 (IL-4), and prostaglandin E₂ (PGE₂) production. TBH MΦ had aberrant regulation of granulocyte-macrophage colony-stimulating factor (GM-CSF). TBH MΦ produced less GM-CSF than normal host (NH) MΦ. GM-CSF failed to increase class II molecule expression on TBH MΦ, and TBH class II⁻ MΦ became more suppressive when cultured with GM-CSF. TBH MΦ GM-CSF dysregulation involved PGE₂ and interleukin-10 (IL-10). Tumor growth also affected CD4⁺ and CD8⁺ T cell phenotype and function. The in vivo percentage of CD8⁺ T cells significantly increased during tumor growth and these cells significantly suppressed T-cell allorecognition and autorecognition. TBH CD8⁺ T-cell suppression was mediated partly through dysregulation of IFN-y, IL-4, and PGE₂ production. TBH CD4⁺ T cells produced less GM-CSF than NH CD4⁺ T cells, and GM-CSF dysregulation was linked partly to increased sensitivity to IL-10 and transforming growth factor-β₁ (TGF-β₁). Tumor growth changed CD4⁺ T cell responsiveness to cytokines associated with T cell activation. TBH CD4⁺ T cell proliferation was suppressed significantly by taxol. This research also suggests that taxol can promote tumor regression. Taxol disrupted tumor cell growth through cytostatic and cytotoxic mechanisms, and increased tumor cell susceptibility to taxol-induced, MΦ-derived lytic molecules. Taxol also disrupted autocrine regulation of TGF-β₁ and stimulated apoptosis. Collectively, these studies suggest that tumor-associated changes in MΦ and T cells involve cytokine dysregulation. |Immunotherapeutic approaches may partly or completely reverse suppressor immune cell activities during tumor growth.

Name thesis:degree_name

Ph. D.

Level thesis:degree_level

doctoral

Discipline thesis:degree_discipline

Biology (Microbiology and Immunology)

Department dc:contributor.department

Biology (Microbiology and Immunology)

Grantor dc:publisher

Virginia Tech

Year dc:date.issued

1995

Author dc:creator

• Walker, Thomas M.

Chair dc:contributor.committeechair

• Elgert, Klaus

Committee members dc:contributor.committeemember

• Ahmed, Sattar Ansar
• Burger, Carol
• Rutherford, Charles L.
• Schurig, Gerhardt

Statement dc:rights

• In Copyright

Licence dc:rights.uri

• http://rightsstatements.org/vocab/InC/1.0/

Language dc:language.iso

en

Dc Identifier Other

etd-02272007-092412

OAI identifier oai:identifier

oai:vtechworks.lib.vt.edu:10919/37436