Rapid release of cytoplasmic IL‐15 from tumor‐associated macrophages is an initial and critical event in IL‐12‐initiated tumor regression

Abstract

This study reveals that the IL-15 rapidly released into serum upon IL-12 injection into tumor-bearing mice is critical for the subsequent leukocytic infiltration of the tumor and tumor-bearing tissue. The increase in serum IL-15 occurs within 2 h after IL-12 injection concomitantly with a decrease in cytoplasmic IL-15 in tumor-associated M/ (TAM). Injection of anti-IL-15 one hour prior to IL-12 abrogates subsequent leukocytic infiltration into the tumor and prevents the IL-12-induced reduction of primary tumor mass and the clearance of metastases. Administration of anti-IL-15 18 h after IL-12 did not have a detectable impact on IL-12-induced leukocytic infiltration of the tumor. Deletion of NK cells had no impact on the IL-12-induced change in the functional phenotype of TAM or on the subsequent initiation of leukocytic infiltration of the tumor. In concert with our previous studies demonstrating that IL-12 reduces tumor-supportive activities of TAM, the current study supports the hypothesis that functional re-programming of TAM not only undermines M/ support for tumor growth but also contributes to a critical step in the initiation of anti-tumor immune responses. In this context, the functional plasticity and pro-immunogenic potential of TAM may constitute a significant and unappreciated target in existing cytokine therapies.

Pigment Epithelium-derived Factor (PEDF) Promotes Tumor Cell Death by Inducing Macrophage Membrane Tumor Necrosis Factor-related Apoptosis-inducing Ligand (TRAIL)

“…TAMs are considered an attractive target for therapeutic intervention. These proposed strategies include activation of TAMs to a tumoricidal state (17)(18)(19), repression of the tumor-supportive activities of TAMs (20), and depletion of TAMs (21)(22)(23). A recent animal study showed that overexpression of PEDF in a rat prostate tumor by transient transfection of a PEDF-expressing plasmid caused increased macrophage recruitment and expression of inducible nitric-oxide synthase in macrophages (12).…”

Nitric oxide short-circuits interleukin-12-mediated tumor regression

“…In addition to direct induction of T, NK, and NKT cell cytotoxicity, IL-12 also promotes macrophage activity via T-and NK-cell-produced IFN [1]. Several studies demonstrated that macrophage activation is critical to the antitumor eVects of this cytokine [2][3][4][5]. SpeciWcally, intratumoral delivery of IL-12 was shown to induce a rapid switch in tumor-associated macrophage (TAM) phenotype from M2 to M1 and release of IL-15, a cytokine that was found to be essential to T-and NK-cell recruitment, and tumor kill [5].…”

“…Several studies demonstrated that macrophage activation is critical to the antitumor eVects of this cytokine [2][3][4][5]. SpeciWcally, intratumoral delivery of IL-12 was shown to induce a rapid switch in tumor-associated macrophage (TAM) phenotype from M2 to M1 and release of IL-15, a cytokine that was found to be essential to T-and NK-cell recruitment, and tumor kill [5]. The role of direct macrophage cytotoxicity in post-IL-12 tumor regression on the other hand is less well deWned [3].…”

TGF-β1, but Not Bone Morphogenetic Proteins, Activates Smad1/5 Pathway in Primary Human Macrophages and Induces Expression of Proatherogenic Genes

“…Macrophages play a highly important role in carcinogenesis, starting from transformed cell control, contributing to tumor initiation by chronic inflammation, and supporting tumor growth and metastasis (1). This high versatility of macrophages and their important role in various diseases prompted researchers worldwide to investigate the possibilities of therapeutic targeting of macrophages or even their use in cell-based therapies (5)(6)(7). Strong arguments in favor of therapeutic targeting of macrophages is provided by recent findings made by us and others demonstrating high levels of macrophage functional plasticity (5,8,9).…”