MDSC and TGFβ Are Required for Facilitation of Tumor Growth in the Lungs of Mice Exposed to Carbon Nanotubes

Abstract

During last decades, changes have been observed in the frequency of different histological subtypes of lung cancer - one of the most common causes of morbidity and mortality - with a declining proportion of squamous cell carcinomas and an increasing proportion of adenocarcinomas, particularly in developed countries. This suggests the emergence of new etiological factors and mechanisms including those defining the lung microenvironment promoting tumor growth. Assuming that the lung is the main portal of entry for broadly used nanomaterials and their established pro-inflammatory propensities, we hypothesized that nanomaterials may contribute to changes facilitating tumor growth. Here we report that an acute exposure to single-walled carbon nanotubes (SWCNT) induces recruitment and accumulation of lung-associated myeloid-derived suppressor cells (MDSC) and MDSC-derived production of TGF-β resulting in up-regulated tumor burden in the lung. The production of TGF-β by MDSC requires their interaction with both SWCNT and tumor cells. We conclude that pulmonary exposure to SWCNT favors the formation of a niche that supports ingrowth of lung carcinoma in vivo via activation of TGF-β production by SWCNT-attracted and pre-sensitized MDSC.

Induction of cancer-associated fibroblast-like cells by carbon nanotubes dictates its tumorigenicity

“…Increasing evidence suggests that certain types of CNTs are carcinogenic7891011123940. Although the mechanism underlying this carcinogenicity remains incompletely understood, an induction of CSCs by CNTs has been implicated1314.…”

“…These results are consistent with the earlier reports showing the modulation of the tumor microenvironment by CNTs that promotes tumor growth. For example, a single pharyngeal aspiration of SWCNT in mice was shown to induce an accumulation of myeloid-derived suppressor cells in the lungs that resulted in host immunosuppression and lung carcinoma acceleration78. The detection of CNT-induced CAF-like cells could be beneficial over the previously reported CNT-induced lung epithelial cell transformation in view of its rapid response to CNT stimuli (e.g.…”

“…Therefore, concern has been raised for the possibility that CNTs would induce an asbestos-like lung cancer or mesothelioma risk456. Several animal studies have indicated the direct and indirect carcinogenic effects of CNTs, i.e., a single aspiration of single-walled (SW) CNT accelerated metastatic growth of lung carcinoma in the mouse model of tumor progression78, while subacute (15-day) inhalation of multi-walled (MW) CNT (Mitsui-7) promoted lung adenocarcinoma in the multi-carcinogenesis mouse model9. MWCNT have also been reported to induce mesothelioma after an intraperitoneal or scrotal injection101112.…”

Myeloid-derived suppressor cells—new and exciting players in lung cancer

“…This effect was mediated by increased local and systemic accumulation of MDSCs [94]. Subsequent studies further revealed that in vivo exposure to CNT rendered lung MDSCs susceptible to tumor-induced expression of TGFβ, which was responsible for the inhibition of T cell activity by MDSCs [95]. Dajon et al, using a murine model of lung adenocarcinoma, found that stimulation of Toll-like receptor 7 (TLR7) expressed by adenocarcinoma cells modulated the immune infiltrate, leading to a significant expansion of MDSCs that was associated with increased secretion of CCL2 and GM-CSF in the tumor microenvironment.…”

Carcinogenic potential of high aspect ratio carbon nanomaterials

“…It was further found that MDSC-derived TGF-β signaling was critical to SWCNT-induced immunosuppression through the inhibition of T-cell activation and proliferation. 62 These findings could lead to the development of screening platforms for evaluating the CNT effects on tumor microenvironment.…”