Host-derived Interleukin-5 Promotes Adenocarcinoma-induced Malignant Pleural Effusion

Abstract

Rationale: IL-5 is a T helper 2 cytokine important in the trafficking and survival of eosinophils. Because eosinophils can be found in malignant pleural effusions (MPE) from mice and humans, we asked whether IL-5 is involved in the pathogenesis of MPE. Objectives: To determine the role of IL-5 in MPE formation. Methods: The effects of IL-5 on experimental MPE induced in C57BL/6 mice by intrapleural injection of syngeneic lung (Lewis lung cancer [LLC]) or colon (MC38) adenocarcinoma cells were determined using wild-type (il5 1/1 ) and IL-5-deficient (il5 2/2 ) mice, exogenous administration of recombinant mouse (rm) IL-5, and in vivo antibody-mediated neutralization of endogenous IL-5. The direct effects of rmIL-5 on LLC cell proliferation and gene expression in vitro were determined by substrate reduction and microarray. Measurements and Main Results: Eosinophils and IL-5 were present in human and mouse MPE, but the cytokine was not detected in mouse (LLC) or human (A549) lung and mouse colon (MC38) adenocarcinoma-conditioned medium, suggesting production by host cells in MPE. Compared with il5 1/1 mice, il5 2/2 mice showed markedly diminished MPE formation in response to both LLC and MC38 cells. Exogenous IL-5 promoted MPE formation in il5 1/1 and il5 2/2 mice, whereas anti-IL-5 antibody treatment limited experimental MPE in il5 1/1 mice. Exogenous IL-5 had no effects on LLC cell proliferation and gene expression; however, IL-5 was found to be responsible for recruitment of eosinophils and tumor-promoting myeloid suppressor cells to MPE in vivo. Conclusions: Host-derived IL-5 promotes experimental MPE and may be involved in the pathogenesis of human MPE.

Malignant pleural effusion: from bench to bedside

“…Finally, host mediators perpetuate this malicious interplay by amplifying inflammatory and angiogenic signalling loops. To this end, host IL-5 promotes MPE by facilitating the pleural influx of eosinophils and tumour-promoting myeloid suppressor cells [35]. In addition, tumour-expressed OPN protects tumour cells from pro-apoptotic stimuli and host-secreted OPN promotes pleural inflammation and angiogenesis, while the cytokine from both origins provokes vascular leakage [30].…”

Tumor-derived osteopontin isoforms cooperate with TRP53 and CCL2 to promote lung metastasis

“…52 In addition, the findings bear implications for future targeting of sSPP1 against metastasis in terms of combined sSPP1/CCL2 inhibition, pretreatment screens for sSPP1/CCL2 expression, and CCL2 blockade against sSPP1-expressing tumors. 48,50,53 In conclusion, we comprehensively mapped the expression patterns, the distinct functions, and the key downstream signaling partners of intracellular and secretory osteopontin isoforms during pulmonary metastasis. We provide proof-of-concept evidence that can be useful for the design of future preclinical and clinical studies aimed at targeting this metastatic trait.…”

“…LLC and B16F10 cells were from the National Cancer Institute Tumor Repository (Frederick, MD); MC38 cells were a gift from Dr Timothy S. Blackwell [Vanderbilt University, Nashville, TN; 53 ; and HEK293T cells were from the American Type Culture Collection (Manassas, VA). Cell lines were cultured in DMEM and tested biannually for identity and stability by short tandem repeats, Sanger sequencing for driver mutations, and microarray.…”

The expanding role(s) of eosinophils in health and disease

“…(2) Tumor infiltrating eosinophils are part of host immune responses that include abilities to polarize T-cell functions, modulate humoral responses, or even be immunosuppressive in character. For example, the presence of IDO-positive eosinophils, 112 release of eosinophil granule proteins, 113 and the presence of IL-5 114 have all been shown to be protumorigenic, whereas in other instances eosinophils are antitumorigenic. 115 Indeed, animal studies addressing the relative role of eosinophils have been confounding.…”