Exosomes derived from Rab27a-overexpressing tumor cells elicit efficient induction of antitumor immunity

Abstract

Lung cancer is the leading cause of mortality worldwide. However, there is a lack of effective therapeutic strategies. Currently, tumor immunotherapy based on exosomes, which are secreted by a variety of cell types including tumor cells, has drawn particular attention and are suggested to have the potential for exploitation in tumor therapy. Nevertheless, the therapeutic efficacy mediated via tumor cell-derived exosomes is not satisfactory. Rab27a, one of the Rab family of small GTPases, has been suggested to be important in exosome secretion. Thus, the purpose of the present study was to examine whether exosomes derived from Rab27a‑overexpressing cells elicited more potent antitumor immunity. A Rab27a‑overexpressing line was established via transfection of a Rab27a overexpression vector into the human non-small-cell lung cancer cell line, A549. Exosomes were isolated and the typical exosomal protein markers, CD9, CD63, heat shock protein (Hsp) 70 and Hsp90, were found to be enriched in the exosomes derived from Rab27a‑overexpressing cells. Subsequently, these exosomes were demonstrated to be capable of upregulating major histocompatibility complex class II molecules as well as the co-stimulatory molecules CD80 and CD86 on dendritic cells (DCs), suggesting that more potent maturation of DCs was induced. Furthermore, DCs loaded with exosomes derived from Rab27-overexpressing cells significantly promoted CD4+ T cell proliferation in vitro. In addition, in vivo immunization of exosomes derived from Rab27a‑overexpressing cells inhibited tumor growth in a mouse model. It was also demonstrated that splenocytes from mice immunized with exosomes derived from Rab27-overexpressing cells expressed high levels of type I cytokines, including IL-2 and IFN-γ, which are important in the regulation of cell-mediated antitumor immunity. Collectively, it was demonstrated that exosomes derived from Rab27a‑overexpressing cancer cells elicited more potent antitumor immune effects, which may provide novel insights for the development of efficient exosome-based cancer vaccines.

Emerging Concepts in Paracrine Mechanisms in Regenerative Cardiovascular Medicine and Biology

“…To this end a number of researchers are actively investigating novel approaches to EV delivery such as incorporating tags to aid in their isolation, over-expression of key cargoes, and designing synthetic EV structures to aid scalability for clinical use 123–125 .…”

The exosomes in tumor immunity

“…HSP70-80, Her2/Neu, Mart1, TRP and gp100 in melanoma, P1A (intracisternal A particle protein) and HSP70 in plasmacytoma cells. [79][80][81] However, these antitumor immune responses induced by TEXs are relatively weak and prone to induce tolerance. Therefore, these strategies are limited to in vitro observations and mouse model studies.…”

“…Exosomes from Rab27a-overexpressing lung cancer cells and OVAexpressing EG7 elicited efficient antitumor immune responses. 81,84 Other successful examples based on this strategy included CD40L-modified lung cancer cells, CIITA-transfected CT26 cells and TNF-engineered J558 tumor cell. [85][86][87] Apart from genetic modification, external stimulus is added to drive tumor cell release of exosomes.…”

Rab GTPases regulate the trafficking of channels and transporters – a focus on cystic fibrosis

“…For instance, using a virtual screening approach, Kang and colleagues identified several ((3,4-dihydroxy benzylidene)-hydrazinyl) pyridine-3-sulfonamide analogs that selectively target Rab27a. 44 Rab27a has been proven necessary for epithelial tumor invasion and metastasis, due to its essential role in exosome secretion, [45][46][47] and these molecules were shown to have significant anti-metastatic effects in breast cancer (MDA-MB231) and melanoma (A375) cell lines. 44 Given the effect of its inhibition on CFTR density at the cell surface, Rab27a was one of the first Rab proteins to be proposed as a putative target in CF disease.…”