Mesothelioma response to carbon nanotubes is associated with an early and selective accumulation of immunosuppressive monocytic cells

Abstract

BackgroundThe asbestos-like toxicity of some engineered carbon nanotubes (CNT), notably their capacity to induce mesothelioma, is a serious cause of concern for public health. Here we show that carcinogenic CNT induce an early and sustained immunosuppressive response characterized by the accumulation of monocytic Myeloid Derived Suppressor Cells (M-MDSC) that counteract effective immune surveillance of tumor cells.MethodsWistar rats and C57BL/6 mice were intraperitoneally injected with carcinogenic multi-walled Mitsui-7 CNT (CNT-7) or crocidolite asbestos. Peritoneal mesothelioma development and immune cell accumulation were assessed until 12 months. Leukocyte sub-populations were identified by recording expression of CD11b/c and His48 by flow cytometry. The immunosuppressive activity on T lymphocytes of purified peritoneal leukocytes was assessed in a co-culture assay with activated spleen cells.ResultsWe demonstrate that long and short mesotheliomagenic CNT-7 injected in the peritoneal cavity of rats induced, like asbestos, an early and selective accumulation of monocytic cells (CD11b/cint and His48hi) which possess the ability to suppress polyclonal activation of T lymphocytes and correspond to M-MDSC. Peritoneal M-MDSC persisted during the development of peritoneal mesothelioma in CNT-7-treated rats but were only transiently recruited after non-carcinogenic CNT (CNT-M, CNT-T) injection. Peritoneal M-MDSC did not accumulate in mice which are resistant to mesothelioma development.ConclusionsOur data provide new insights into the initial pathogenic events induced by CNT, adding a new component to the adverse outcome pathway leading to mesothelioma development. The specificity of the M-MDSC response after carcinogenic CNT exposure highlights the interest of this response for detecting the ability of new nanomaterials to cause cancer.Electronic supplementary materialThe online version of this article (doi:10.1186/s12989-016-0158-0) contains supplementary material, which is available to authorized users.

How asbestos drives the tissue towards tumors: YAP activation, macrophage and mesothelial precursor recruitment, RNA editing and somatic mutations

“…Mesothelin-deficient mice have a normal phenotype (Bera and Pastan, 2000) and to our knowledge no study has been performed using mesothelin-deficient mice exposed to asbestos to check whether mesothelin deficiency would affect tumor development. However, to address this question it should be kept in mind that the penetrance of the disease after exposure to asbestos fibers in C57BL/6 genetic background is unexpectedly low (10% in this study using Nf2 heterozygotes mice), consistent with other studies (Huaux et al, 2016, Napolitano et al, 2015, therefore further refinements of the model would be necessary before starting such investigation.…”

“…The impact of host factors to promote tumor growth is also supported by the observation that less than 50% of human mesothelioma grow in NOD/SCID mice (Tsao et al, 2016), (Felley-Bosco, unpublished), possibly due to an unfavorable growth microenvironment. As mentioned previously, macrophages are recruited to the site of damage after administration of a single dose of asbestos fibers (Moalli et al, 1987) and it has been recently confirmed that this population is the most abundant after intraperitoneal administration of asbestos in C57Bl/6J mice (Huaux et al, 2016). A role for macrophages in asbestos-related chronic inflammation had been suggested in functional studies where "frustrated phagocytosis" induced by exposure of macrophages to asbestos increased the secretion of mature interleukin-1β by activating the complex Nod-like receptor (NLR)-pyrin domain containing 3, Nlrp3, procaspase-1, and the ASC (apoptosis speck-like protein containing a CARD) adapter, which bridges interactions between the former proteins (Dostert et al, 2008).…”

<p>Toxicity of Carbon Nanotubes as Anti-Tumor Drug Carriers</p>

“…93 However, these pathways may be involved in the development of fibrosis, leading to cytotoxicity and apoptosis of normal cells. Huaux et al 97 proposed immunosuppression as another mechanism of CNT-induced cytotoxicity. In their experiments, a specific type of CNT, Mitsui-7 CNT, was injected into the peritoneal cavity of Wistar rats and C57BL/6 mice for 12 months, and development of mesothelioma and monocytic myeloid-derived suppressor cells (M-Changes in MDSC) were examined.…”

Conventional and novel “omics”‐based approaches to the study of carbon nanotubes pulmonary toxicity

“…DOI 10.1002/em Conventional and ''Omics'' CNT Toxicity Studies (Sakamoto et al, 2009) and lung carcinomas after wholebody inhalation exposure of male rats (0.2-2 mg/m 3 ) and female rats (2 mg/m 3 ; Kasai et al, 2016). These cells possess the ability to suppress polyclonal activation of T lymphocytes and correspond to M-MDSC, counteracting the effective immune surveillance of tumor cells (Huaux et al, 2016). In another study, Mitsui-7 injection in the peritoneal cavity of rats induced, like asbestos, an early and selective sustained immunosuppressive response characterized by the accumulation of monocytic Myeloid Derived Suppressor Cells (CD11b/cint and His48hi).…”

“…In another study, Mitsui-7 injection in the peritoneal cavity of rats induced, like asbestos, an early and selective sustained immunosuppressive response characterized by the accumulation of monocytic Myeloid Derived Suppressor Cells (CD11b/cint and His48hi). These cells possess the ability to suppress polyclonal activation of T lymphocytes and correspond to M-MDSC, counteracting the effective immune surveillance of tumor cells (Huaux et al, 2016).…”