IL-4 blockade alters the tumor microenvironment and augments the response to cancer immunotherapy in a mouse model

Abstract

Recent findings show that immune cells constitute a large fraction of the tumor microenvironment and that they modulate tumor progression. Clinical data indicate that chronic inflammation is present at tumor sites and that IL-4, in particular, is upregulated. Thus, we tested whether IL-4 neutralization would affect tumor immunity. Current results demonstrate that the administration of a neutralizing antibody against IL-4 enhances anti-tumor immunity and delays tumor progression. IL-4 blockade also alters inflammation in the tumor microenvironment, reducing the generation of both immunosuppressive M2 macrophages and myeloid-derived suppressor cells, and enhancing tumor-specific cytotoxic T lymphocytes. In addition, IL-4 blockade improves the response to anti-OX40 Ab or CpG oligodeoxynucleotide immunotherapies. These findings suggest that IL-4 affects anti-tumor immunity and constitutes an attractive therapeutic target to reduce immune suppression in the tumor microenvironment, thus enhancing the efficacy of cancer therapy.

FPR2 Participates in Epithelial Ovarian Cancer (EOC) Progression Through RhoA Mediated M2 Macrophage Polarization: An Invitro Experimental Study

“…Studies revealed that IL-4 antibody neutralization enhances anti-tumor immunity and delays tumor progression. IL-4 blockade also alters in ammation in the tumor microenvironment, reducing the generation of both immunosuppressive M2 macrophages and myeloid-derived suppressor cells, and enhancing tumorspeci c cytotoxic T lymphocytes [24]. In our study, we found that FPR2 played an auxo-action on secretion of IL-10 and IL-4 in ovarian cancer cells, and induction of M2 macrophages polarization.…”

CD4 and CD8 T lymphocyte interplay in controlling tumor growth

“…If Th2 responses are elicited in consequence of alternatively activated macrophages in the tumor tissue, it promotes the formation of an immunosuppressive microenvironment as shown in patients with esophageal cancer [ 133 ]. This was a central issue in a recent study by Ito et al, showing that blocking IL-4 changes the microenvironment of the tumor to the favor of Th1-polarization from Th2 in mice, suggesting a possible enhancement of human immunotherapy by IL-4 mAb treatment [ 134 ]. Pharmacologic interventions can also have a significant effect on Th17 responses in mouse models [ 135 ].…”

The Crosstalk Between Tumor-Associated Macrophages (TAMs) and Tumor Cells and the Corresponding Targeted Therapy

“…These results also indicate that IFN-g and IL-4 play an antagonistic role in the differentiation of TAMs and that targeting IL-4 in the TME may contribute to lung cancer treatment. Indeed, it has been found that targeting the elevated IL-4 in the TME also alters inflammation in the tumor microenvironment, reducing the generation of immunosuppressive M2 macrophages and myeloid-derived suppressor cells (MDSCs), which enhances anti-tumor immunity and delays tumor progression (41). Moreover, tumor-derived CSF-1 and IL-4 synergistically induce M2-type polarization of macrophages (42).…”