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 (MΦ) that ultimately lead to the immunosuppression of the tumor-bearing host (TBH). To investigate the phenotypic changes of MΦ during tumor growth, we examined the expression of the MΦ surface antigens, Mac-1, Mac-2, Mac-3, and Ia on peritoneal and splenic MΦ. In the peritoneal cavity there was no change in the percentage of Mac-1⁺ MΦ but a decrease in the percentage of Mac-2⁺, -3⁺, and Ia⁺ MΦ during tumor growth. In addition, three distinctly sized populations of peritoneal MΦ, showing differential antigen expression, also shifted during tumor growth. In the peritoneal cavity there was a decrease in the percentage of MΦ co-expressing the Mac-2, -3, and Ia antigens, leading to a shift towards Mac-1⁺ 2⁻ 3⁻ Ia⁻ TBH MΦ. In splenic MΦ, the percentage of Mac-1⁺, -2⁺, and -3⁺ MΦ increased, while the percentage of Ia⁺ MΦ decreased. Splenic MΦ showed an increase in the percentage of MΦ co-expressing Mac-1, -2, and -3 antigens and a decrease in the percentage of MΦ co-expressing Ia, leading to a shift towards a Mac-1⁺ 2⁺ 3⁺ Ia⁻ TBH MΦ. Taken together, these data suggest that tumor growth alters the phenotype of MΦ and causes a shift in MΦ subpopulations. After measuring the phenotypic changes in MΦ during tumor growth, changes in MΦ accessory function to T cells were assessed. TBH MΦ 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 MΦ down-regulated autoreactive T cell responsiveness to interleukin (IL)-1, IL-2, and IL-4. In addition to TBH MΦ 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 MΦ to activation signals, lipopolysaccharide (LPS) was incubated with normal and TBH splenic MΦ and assessed for their phenotypic, functional, and cell-cycle changes. The data showed that TBH MΦ had a decreased responsiveness to LPS. We showed that there was a shift from an Ia⁺ MΦ in the normal host to an Ia⁻ MΦ in the TBH. Concomitant with the shift in TBH MΦ Ia⁻ phenotype was a change in TBH MΦ function. Normal and TBH Ia⁻ MΦ were suppressor MΦ. TBH Ia⁻ MΦ, 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 MΦ. Although Ia⁻ MΦ-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.