The association of tumor-induced changes in macrophage phenotype with immunosuppressive functions

Abstract

During tumor growth there are a series of phenotypic and functional changes that occur in macrophages (M_Φ) that ultimately lead to the immunosuppression of the tumor-bearing host (TBH). To investigate the phenotypic changes of M_Φ during tumor growth, we examined the expression of the M_Φ surface antigens, Mac-1, Mac-2, Mac-3, and Ia on peritoneal and splenic M_Φ. In the peritoneal cavity there was no change in the percentage of Mac-1⁺ M_Φ but a decrease in the percentage of Mac-2⁺, -3⁺, and Ia⁺ M_Φ during tumor growth. In addition, three distinctly sized populations of peritoneal M_Φ, showing differential antigen expression, also shifted during tumor growth. In the peritoneal cavity there was a decrease in the percentage of M_Φ co-expressing the Mac-2, -3, and Ia antigens, leading to a shift towards Mac-1⁺ 2⁻ 3⁻ Ia⁻ TBH M_Φ. In splenic M_Φ, the percentage of Mac-1⁺, -2⁺, and -3⁺ M_Φ increased, while the percentage of Ia⁺ M_Φ decreased. Splenic M_Φ showed an increase in the percentage of M_Φ co-expressing Mac-1, -2, and -3 antigens and a decrease in the percentage of M_Φ co-expressing Ia, leading to a shift towards a Mac-1⁺ 2⁺ 3⁺ Ia⁻ TBH M_Φ. Taken together, these data suggest that tumor growth alters the phenotype of M_Φ and causes a shift in M_Φ subpopulations.

After measuring the phenotypic changes in M_Φ during tumor growth, changes in M_Φ accessory function to T cells were assessed. TBH M_Φ have significantly reduced accessory activity for autoreactive T cells. This reduction is caused by decreased Ia antigen expression and increased production of the suppressor molecule, prostaglandin (PG). TBH M_Φ down-regulated autoreactive T cell responsiveness to interleukin (IL)-1, IL-2, and IL-4. In addition to TBH M_Φ reducing T cell responsiveness to cytokines, TBH CD4⁺ T cells alone were less responsive to the cytokines IL-1, IL-2, and IL-4. To examine the responsiveness of M_Φ to activation signals, lipopolysaccharide (LPS) was incubated with normal and TBH splenic M_Φ and assessed for their phenotypic, functional, and cell-cycle changes. The data showed that TBH M_Φ had a decreased responsiveness to LPS.

We showed that there was a shift from an Ia⁺ M_Φ in the normal host to an Ia⁻ M_Φ in the TBH. Concomitant with the shift in TBH M_Φ Ia⁻ phenotype was a change in TBH M_Φ function. Normal and TBH Ia⁻ M_Φ were suppressor M_Φ. TBH Ia⁻ M_Φ, however, suppressed autoreactive and alloreactive CD4⁺ T cells significantly more than could their normal counterparts. Tumor growth causes quantitative and qualitative changes in Ia⁻ suppressor M_Φ. Although Ia⁻ M_Φ-mediated suppression seemed to be the major source of down-regulation of CD4⁺ T cells, CD8⁺ T cells were not without fault. In the TBH, there was an increase in the percentage of CD8⁺ T cells and an increase in CD8⁺ T cell-mediated suppression. In conclusion, tumor growth leads to a change in immunoregulation that causes suppression of the immune response.