Improvement of Macrophage Dysfunction by Administration of Anti‐transforming Growth Factor‐β Antibody in EL4‐bearing Hosts

Abstract

An experimental therapy for improvement of macrophage dysfunction caused by transforming growth factor‐β (TGF‐β) was tried in EL4 tumor‐bearing mice. TGF‐β was detected in cell‐free ascitic fluid from EL4‐bearers, but not in tbat from normal mice, by western blot analysis. The ascites also showed growth‐suppressive activity against MvlLn cells, and the suppressive activity was potentiated by transient acidification. To investigate whether the functions of peritoneal macrophagcs were suppressed in EL4‐bearers, the abilities to produce nitric oxide and tumor necrosis factor‐α (TNF‐α) upon lipopolysaccharide (LPS) stimulation were measured. Both abilities of macrophages in EL4‐bearing mice were suppressed remarkably on day 9, and decreased further by day 14, compared with non‐tumor‐bearing controls. TGF‐β activity was abrogated by administration of anti‐TGF‐α antibody to EL4‐bearing mice. While a large amount of TGF‐β was detected in ascitic fluid from control EL4‐bearers, little TGF‐β was detectable in ascites from EL4‐bearers given anti‐TGF‐β antibody. Furthermore, while control macrophages exhibited little or no production of nitric oxide and TNF‐α on LPS stimulation in vitro, macrophages from EL4‐bearers administered with anti‐TGF‐β antibody showed the same ability as normal macrophages. These results clearly indicate that TGF‐β contributes to macrophage dysfunction and that the administration of specific antibody for TGF‐β reverses macrophage dysfunction in EL4‐bearing hosts.

Transforming Growth Factor-β Receptor Blockade Augments the Effectiveness of Adoptive T-Cell Therapy of Established Solid Cancers

“…The increased levels of inducible nitric oxide synthase, IL-12, and tumor necrosis factor-a suggest that TGF-h blockade produces a more TH-1 -like environment and likely affects the tumor-associated macrophage phenotype favoring a more M1 (cytotoxic) versus M2 (alternatively activated) phenotype (23,24,53). This observation is consistent with an earlier report showing improvement of macrophage dysfunction by administration of anti -TGF-h antibody in EL4-bearing hosts (54). Furthermore, a decrease in tumor arginase levels would also be expected to augment T-cell persistence and function (25).…”

Immunopotentiating effect of proton pump inhibitor pantoprazole in a lymphoma-bearing murine host: Implication in antitumor activation of tumor-associated macrophages

“…These observations also strongly indicate the possibility that TAM of PPZ-administered tumor-bearing mice have either shifted to M1 phenotype and/or PPZ administration triggers recruitment of M1 macrophages in tumor microenvironment. Nevertheless, production of TNF-␣ and NO is considered as functional markers of M1 macrophages [40]. Moreover, it has been reported that IL-6 and IFN-␥ promote M1 macrophage differentiation, while IL-10 and TGF-␤ have been shown to promote M2 type of macrophages [36,13,40].…”

“…Nevertheless, production of TNF-␣ and NO is considered as functional markers of M1 macrophages [40]. Moreover, it has been reported that IL-6 and IFN-␥ promote M1 macrophage differentiation, while IL-10 and TGF-␤ have been shown to promote M2 type of macrophages [36,13,40]. We observed that PPZ-treated tumor cells showed a declined production of IL-4, IL-10 and TGF-␤ with an elevation of IL-6 and IFN-␥ in the culture supernatant of tumor cells, thus such alteration of the tumor microenvironment may favor polarization of M1 macrophages.…”