Abstract
BackgroundProgranulin (PGRN), as a multifunctional growth factor, is overexpressed in multiple tumors, but the role of PGRN on tumor immunity is still unclear. Here, we studied the effect of PGRN on breast cancer tumor immunity and its possible molecular mechanism.MethodsThe changes of macrophage phenotypes after PGRN treatment were detected by western blot, quantitative polymerase chain reaction (PCR) and flow cytometry. Western blot was used to study the signal molecular mechanism of PGRN regulating this process. The number and localization of immune cells in Wild-type (WT) and PGRN−/− breast cancer tissues were analyzed by immunohistochemical staining and immunofluorescence techniques. The activation and proliferation of CD8+ T cells were measured by flow cytometry.ResultsAfter being treated with PGRN, the expressions of M2 markers and programmed death ligand 1 (PD-L1) on macrophages increased significantly. Signal transducer and activator of transcription 3 (STAT3) signaling pathway inhibitor Stattic significantly inhibited the expression of PD-L1 and M2 related markers induced by PGRN. In WT group, CD8 were co-localized with macrophages and PD-L1, but not tumor cells. The number of immune cells in PGRN−/− breast cancer tissue increased, and their infiltration into tumor parenchyma was also enhanced. Moreover, in the co-culture system, WT peritoneal macrophages not only reduced the ratio of activated CD8+ T cells but also reduced the proportion of proliferating CD8+ T cells. The addition of programmed death receptor 1 (PD-1) and PD-L1 neutralizing antibodies effectively reversed this effect and restored the immune function of CD8+ T cells.ConclusionThese results demonstrate that PGRN promotes M2 polarization and PD-L1 expression by activating the STAT3 signaling pathway. Furthermore, through PD-1/PD-L1 interaction, PGRN can promote the breast tumor immune escape. Our research may provide new ideas and targets for clinical breast cancer immunotherapy.
Highlights
In recent years, as an emerging treatment, breast cancer immunotherapy has attracted tons of attention [1], especially systemic therapies mediated by programmed death ligand 1 (PD-L1) [2]
We demonstrated that PGRN up-regulated the PD-L1 expression of tumor-associated macrophages (TAMs) through JAK/Signal transducer and activator of transcription 3 (STAT3) signaling pathway and promoted the polarization of TAMs to M2 macrophages
We found that PGRN reduced inducible nitric oxide synthase (iNOS) and CD86 expression, and increased arginase 1 (Arg1) and CD206 expression (Fig. 1d; Supplementary Figure S1A, B)
Summary
As an emerging treatment, breast cancer immunotherapy has attracted tons of attention [1], especially systemic therapies mediated by programmed death ligand 1 (PD-L1) [2]. PD-L1 can cause T cell dysfunction and failure, prevents cytotoxic T cells from effectively targeting tumor cells via binding to the programmed death receptor 1 (PD-1) on T cells, and promotes the occurrence and development of tumors [4, 5]. The expression of PD-L1 on TAMs is more sustaining than those on tumor cells [8]. Progranulin (PGRN), as a multifunctional growth factor, is overexpressed in multiple tumors, but the role of PGRN on tumor immunity is still unclear. We studied the effect of PGRN on breast cancer tumor immunity and its possible molecular mechanism
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
