IL-4 induces cathepsin protease activity in tumor-associated macrophages to promote cancer growth and invasion

Abstract

Innate immune cells can constitute a substantial proportion of the cells within the tumor microenvironment and have been associated with tumor malignancy in patients and animal models of cancer; however, the mechanisms by which they modulate cancer progression are incompletely understood. Here, we show that high levels of cathepsin protease activity are induced in the majority of macrophages in the microenvironment of pancreatic islet cancers, mammary tumors, and lung metastases during malignant progression. We further show that tumor-associated macrophage (TAM)-supplied cathepsins B and S are critical for promoting pancreatic tumor growth, angiogenesis, and invasion in vivo, and markedly enhance the invasiveness of cancer cells in culture. Finally, we demonstrate that interleukin-4 (IL-4) is responsible for inducing cathepsin activity in macrophages in vitro and in vivo. Together, these data establish IL-4 as an important regulator, and cathepsin proteases as critical mediators, of the cancer-promoting functions of TAMs.[Keywords: Tumor-associated macrophage; tumor microenvironment; cysteine cathepsin; protease; interleukin-4; invasion] Supplemental material is available at http://www.genesdev.org.

Improving Chimeric Antigen Receptor-Modified T Cell Function by Reversing the Immunosuppressive Tumor Microenvironment of Pancreatic Cancer

“…45,46 In this study, we evaluated the potential benefit of combining the 4/7 ICR with a tumor-specific CAR for the treatment of pancreatic cancer where elevated IL-4 and PSCA levels correlate with advanced disease, enhanced metastatic potential, and accelerated tumor growth. 7,15,16,18,24,47 Therefore, by sequestering IL-4, our approach has the added benefit of depriving tumor cells of a growth factor while simultaneously transforming an inherently inhibitory signal to one that will promote effector T cell function. We selected the IL-7 receptor endodomain component of our ICR since this cytokine is a prototypic Th1 cytokine, 48,49 and both IL-4 and IL-7 are common gamma chain cytokines.…”

“…12 However, malignant cells comprise only 10%-40% of the tumor, 13,14 while the rest is a complex desmoplastic matrix consisting of extracellular proteins, stellate cells, and immunomodulatory cells that produce cytokines including interleukin-4 (IL-4), IL-10, and transforming growth factor b (TGF-b) that promote fibrogenesis, support tumor growth and protect malignant cells from immune destruction. [15][16][17][18][19][20] Thus, in order to provide clinical benefit to patients with PDAC, it is likely that the tumor-targeting T cells will require additional engineering to enable them to withstand this hostile environment.…”

Characterization of intratumoral follicular helper T cells in follicular lymphoma: role in the survival of malignant B cells

“…Of note, beside its survival potential, IL-4 was also able to drive macrophages toward a TAM phenotype endowed with tumor invasion, immunoregulatory and pro-angiogenic properties. 51 In summary, our results depict new facets of the complex cellular interactions in FL and highlight the important supportive role of T FH in the tumor microenvironment of FL malignant B cells. Targeting T FH and their survival factors in combination with direct antitumor agents might be a promising strategy to provide new therapeutic schemes for FL patients.…”

Three‐dimensional invasion of macrophages is mediated by cysteine cathepsins in protrusive podosomes

“…A recent study showed that mouse Mfs lacking CtsB or S (from CtsB −/− RT2 and CtsS −/− RT2 mice) were defective in invading ECM substrates, markedly reducing the invasive ability of cocultured cancer cells [24]. Moreover, cathepsin B was shown to be involved in the podosome-mediated degradation of ECM in v-Src transformed mouse fibroblasts [25].…”