Abstract
Immunostimulatory gene therapy utilizing oncolytic viruses (OVs) as gene vehicles is a promising immunotherapy for cancer. Since viruses are immunogenic, systemic delivery can be troublesome due to neutralizing antibodies. Nevertheless, local delivery by intratumoral injection seems to induce systemic immune reactions. In this study, we demonstrate a novel mechanism of action of armed OV therapy suggesting that exosomes released by tumor cells infected with armed OV may participate to activate the immune system and this may also support systemic immunity. Tumor cell-derived exosomes commonly exert immunosuppressive functions. We hypothesized that exosomes derived from OV-infected tumor cells may instead be immunostimulatory. Human melanoma cells were infected by OVs armed with costimulatory molecules CD40 ligand (CD40L) and 4-1BB ligand (4-1BBL). Exosomes were purified and investigated for the presence of CD40L/4-1BBL mRNA and protein, and for their capacity to stimulate immune responses. The results show that the exosomes cargo transgenes. The exosomes from CD40L/4-1BBL-expressing tumor cells, or the viruses themselves, could stimulate robust dendritic cell (DC) activation with an enhanced level of major histocompatibility complex (MHC) and costimulatory molecules. Hence, exosomes after OV infection can locally activate immune responses at the tumor site and encounter immune cells such as DCs.
Highlights
The tumor microenvironment (TME) is heterogeneous and complex
Clinical outcomes depend on the level of tumor-infiltrating lymphocytes (TILs) in the TME, as an augmentation of CD4+, CD8+, and natural killer (NK) cells in the early stage of a malignant tumor is associated with a favorable prognosis
Such a treatment depends on pre-existing immune reactive TILs, and for non-responsive or refractory tumors there is a need to develop immunotherapies that activate de novo immune responses as well as boosting pre-existing immunity to sensitize “cold” tumors to checkpoint inhibition (CPI)
Summary
The tumor microenvironment (TME) is heterogeneous and complex. As shown in several cancer types, the presence of tumor-infiltrating lymphocytes (TILs) in solid tumors is an attribution of better prognosis.[1]. As a member of the tumor necrosis factor (TNF) ligand family, 4-1BBL is endogenously expressed on activated APCs, T cells, and several carcinoma cell lines.[8,9,10] Engagement of 4-1BBL with its receptor, 4-1BB, promotes costimulatory signal transduction in CD4+ and CD8+ T cells, leading to their activation and expansion of CD8+ T cells with enhanced IFN-g production.[8] Naturally found CD40L is expressed on activated B cells, T cells, platelets, monocytes, natural killer (NK) cells, basophils, and mast cells.[11] Interaction between CD40L and its receptor culminates in DC maturation and activation.[11] When LOAd viruses infect tumor cells, they can replicate, reprogram the cells to express the transgenes, and display them as membrane-bound proteins They induce antitumor responses either directly or indirectly through DCs. We hypothesized that LOAd-infected tumor cells expressing the transgenes may pack them into the endosomal compartments and release them via a subtype of extracellular vesicles known as exosomes. Such transgene-expressing exosomes may participate to elicit the antitumor responses locally and likely at distant sites from the tumor
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